U.S. patent application number 15/044231 was filed with the patent office on 2016-06-09 for pyrazolo[3,4-c]pyridine compounds and methods of use.
This patent application is currently assigned to Genentech, Inc.. The applicant listed for this patent is Genentech, Inc.. Invention is credited to Steven Do, Huiyong Hu, Aleksandr Kolesnikov, Wendy Lee, Vickie Hsiao-Wei Tsui, Xiaojing Wang, Zhaoyang Wen.
Application Number | 20160159797 15/044231 |
Document ID | / |
Family ID | 46717823 |
Filed Date | 2016-06-09 |
United States Patent
Application |
20160159797 |
Kind Code |
A1 |
Do; Steven ; et al. |
June 9, 2016 |
PYRAZOLO[3,4-c]PYRIDINE COMPOUNDS AND METHODS OF USE
Abstract
Pyrazolo[3,4-c]pyridine compounds of Formula I, including
stereoisomers, geometric isomers, tautomers, and pharmaceutically
acceptable salts thereof, wherein R.sup.1 and R.sup.2 are as
defined herein, are useful for inhibiting Pim kinase, and for
treating disorders such as cancer mediated by Pim kinase. Methods
of using compounds of Formula I for in vitro, in situ, and in vivo
diagnosis, prevention or treatment of such disorders in mammalian
cells, or associated pathological conditions, are disclosed.
##STR00001##
Inventors: |
Do; Steven; (San Jose,
CA) ; Hu; Huiyong; (San Mateo, CA) ;
Kolesnikov; Aleksandr; (San Francisco, CA) ; Lee;
Wendy; (San Ramon, CA) ; Tsui; Vickie Hsiao-Wei;
(Burlingame, CA) ; Wang; Xiaojing; (Foster City,
CA) ; Wen; Zhaoyang; (San Francisco, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Genentech, Inc. |
South San Francisco |
CA |
US |
|
|
Assignee: |
Genentech, Inc.
South San Francisco
CA
|
Family ID: |
46717823 |
Appl. No.: |
15/044231 |
Filed: |
February 16, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13571595 |
Aug 10, 2012 |
9260425 |
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15044231 |
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61522857 |
Aug 12, 2011 |
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Current U.S.
Class: |
424/133.1 ;
514/110; 514/171; 514/210.21; 514/217.07; 514/218; 514/249;
514/253.04; 514/255.05; 514/256; 514/286; 514/303; 514/34; 514/64;
514/83; 540/575; 540/597; 544/333; 544/349; 544/362; 544/405;
546/119 |
Current CPC
Class: |
A61P 35/02 20180101;
A61P 29/00 20180101; A61K 45/06 20130101; A61P 31/00 20180101; C07D
231/00 20130101; A61P 3/00 20180101; A61P 35/00 20180101; A61P
37/00 20180101; A61P 25/00 20180101; A61K 31/4995 20130101; A61K
31/497 20130101; A61K 31/55 20130101; A61K 31/506 20130101; A61P
43/00 20180101; A61K 31/437 20130101; C07D 471/04 20130101; A61P
31/12 20180101; C07D 519/00 20130101; A61K 31/496 20130101; A61K
31/551 20130101; A61P 37/02 20180101; A61P 5/00 20180101; A61P 9/00
20180101 |
International
Class: |
C07D 471/04 20060101
C07D471/04; A61K 31/497 20060101 A61K031/497; A61K 31/506 20060101
A61K031/506; A61K 45/06 20060101 A61K045/06; A61K 31/55 20060101
A61K031/55; A61K 31/551 20060101 A61K031/551; C07D 519/00 20060101
C07D519/00; A61K 31/4995 20060101 A61K031/4995; A61K 31/437
20060101 A61K031/437; A61K 31/496 20060101 A61K031/496 |
Claims
1. A compound selected from Formula I: ##STR00521## and
stereoisomers, geometric isomers, tautomers, or pharmaceutically
acceptable salts thereof, wherein: R.sup.1 is selected from --CN,
--CH.sub.2CN, --CH.sub.2CONH.sub.2, --CONH.sub.2, --CONHCH.sub.3,
--CON(CH.sub.3).sub.2, --NHCONH.sub.2, carbocyclyl,
C.sub.2-C.sub.20 heterocyclyl, C.sub.1-C.sub.20 heteroaryl,
--(C.sub.1-C.sub.20 heteroaryl)-(C.sub.1-C.sub.20 heteroaryl),
--(C.sub.1-C.sub.20 heteroaryl)-(C.sub.2-C.sub.20 heterocyclyl),
--(C.sub.1-C.sub.20 heteroaryl)-O--(C.sub.2-C.sub.20 heterocyclyl),
--(C.sub.1-C.sub.20 heteroaryl)-O--(C.sub.1-C.sub.12
alkylene)-(C.sub.2-C.sub.20 heterocyclyl), --(C.sub.1-C.sub.20
heteroaryl)-NR.sup.3--(C.sub.2-C.sub.20 heterocyclyl), and
--(C.sub.1-C.sub.20 heteroaryl)-NR.sup.3--(C.sub.1-C.sub.12
alkylene)-(C.sub.2-C.sub.20 heterocyclyl); R.sup.2 is selected from
C.sub.1-C.sub.12 alkyl, C.sub.3-C.sub.12 carbocyclyl,
C.sub.2-C.sub.20 heterocyclyl, C.sub.1-C.sub.20 heteroaryl,
C.sub.6-C.sub.20 aryl, --(C.sub.6-C.sub.20 aryl)-(C.sub.2-C.sub.20
heterocyclyl), --(C.sub.1-C.sub.12 alkylene)-(C.sub.2-C.sub.20
heterocyclyl), --(C.sub.1-C.sub.12
alkylene)-NR.sup.3(C.sub.2-C.sub.20 heterocyclyl),
--(C.sub.1-C.sub.12 alkylene)-NR.sup.3--(C.sub.1-C.sub.12
alkylene)-(C.sub.2-C.sub.20 heterocyclyl), --(C.sub.1-C.sub.20
heteroaryl)-(C.sub.1-C.sub.20 heteroaryl), --(C.sub.1-C.sub.20
heteroaryl)-(C.sub.2-C.sub.20 heterocyclyl), --(C.sub.1-C.sub.20
heteroaryl)-(C.sub.2-C.sub.20 heterocyclyl)-(C.sub.2-C.sub.20
heterocyclyl), --(C.sub.1-C.sub.20
heteroaryl)-NR.sup.3--(C.sub.2-C.sub.20 heterocyclyl),
--(C.sub.1-C.sub.20 heteroaryl)-(C.sub.1-C.sub.12
alkylene)-(C.sub.2-C.sub.20 heterocyclyl), --(C.sub.1-C.sub.20
heteroaryl)-NR.sup.3--(C.sub.1-C.sub.12 alkylene)-(C.sub.2-C.sub.20
heterocyclyl), and --(C.sub.1-C.sub.20
heteroaryl)-NR.sup.3--(C.sub.1-C.sub.12 alkylene)-(C.sub.1-C.sub.20
heteroaryl); R.sup.3 is independently selected from H and
C.sub.1-C.sub.12 alkyl optionally substituted with F, Cl, CN,
--CO.sub.2H, --COCH.sub.3, --CO.sub.2CH.sub.3,
--CO.sub.2C(CH.sub.3).sub.3, --COCH(OH)CH.sub.3, --CONH.sub.2,
CONHCH.sub.3, --CON(CH.sub.3).sub.2, --NO.sub.2, --NH.sub.2,
--NHCH.sub.3, --N(CH.sub.3).sub.2, --NHCOCH.sub.3,
--N(CH.sub.3)COCH.sub.3, --NHS(O).sub.2CH.sub.3,
--NHCH.sub.2CH.sub.2NH.sub.2, --NHCH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--N(CH.sub.3)C(CH.sub.3).sub.2CONH.sub.2,
--N(CH.sub.3)CH.sub.2CH.sub.2S(O).sub.2CH.sub.3, .dbd.O, --OH,
--OCH.sub.3, --OCH.sub.2CH.sub.2OCH.sub.3,
--OCH.sub.2CH.sub.2NH.sub.2, --S(O).sub.2N(CH.sub.3).sub.2,
--SCH.sub.3, and --S(O).sub.2CH.sub.3; where alkyl, alkenyl,
alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl
are optionally substituted with one or more groups independently
selected from F, Cl, Br, I, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH(CH.sub.3).sub.2,
--CH.sub.2NH.sub.2, --CH.sub.2NHCH.sub.3,
--CH.sub.2N(CH.sub.3).sub.2, --CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CHCH.sub.2NH.sub.2, --CH.sub.2CHCH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH(CH.sub.3)NH.sub.2, --CH.sub.2CONH.sub.2, --CH.sub.2OH,
--CH.sub.2CH.sub.2OH, --C(CH.sub.3).sub.2OH,
--CH(OH)CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.2CH.sub.2OH,
--CH.sub.2C(CH.sub.3).sub.2OH, --CH.sub.2CH.sub.2SO.sub.2CH.sub.3,
--CN, --CF.sub.3, --CO.sub.2H, --COCH.sub.3, --CO.sub.2CH.sub.3,
--CO.sub.2C(CH.sub.3).sub.3, --COCH(OH)CH.sub.3, --CONH.sub.2,
--CONHCH.sub.3, --CON(CH.sub.3).sub.2,
--C(CH.sub.3).sub.2CONH.sub.2, --NO.sub.2, --NH.sub.2,
--NHCH.sub.3, --N(CH.sub.3).sub.2, --NHCOCH.sub.3,
--N(CH.sub.3)COCH.sub.3, --NHS(O).sub.2CH.sub.3,
--NHCH.sub.2CH.sub.2NH.sub.2, --NHCH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--N(CH.sub.3)C(CH.sub.3).sub.2CONH.sub.2,
--N(CH.sub.3)CH.sub.2CH.sub.2S(O).sub.2CH.sub.3, .dbd.O, --OH,
--OCH.sub.3, --OCH.sub.2CH.sub.2OCH.sub.3,
--OCH.sub.2CH.sub.2NH.sub.2, --S(O).sub.2N(CH.sub.3).sub.2,
--SCH.sub.3, --CH.sub.2OCH.sub.3, --S(O).sub.2CH.sub.3,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl,
piperidinyl, (piperidin-4-yl)ethyl), pyranyl,
(piperidin-4-ylmethyl), morpholinomethyl, and morpholino.
2. The compound of claim 1 wherein R.sup.1 is C.sub.1-C.sub.20
heteroaryl.
3. The compound of claim 1 wherein R.sup.1 is selected from the
structures: ##STR00522## where the wavy line indicates the site of
attachment.
4. The compound of claim 1 wherein R.sup.1 is selected from --CN,
--CH.sub.2CN, --CH.sub.2CONH.sub.2, --CONH.sub.2, --CONHCH.sub.3,
--CON(CH.sub.3).sub.2, and --NHCONH.sub.2.
5. The compound of claim 1 wherein R.sup.2 is C.sub.1-C.sub.20
heteroaryl.
6. The compound of claim 1 wherein R.sup.2 is --(C.sub.1-C.sub.20
heteroaryl)-(C.sub.2-C.sub.20 heterocyclyl).
7. The compound of claim 1 wherein R.sup.2 is selected from the
structures: ##STR00523## where the wavy line indicates the site of
attachment; and R.sup.4 is selected from F, Cl, Br, I, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2,
--CH.sub.2CH(CH.sub.3).sub.2, --CH.sub.2NH.sub.2,
--CH.sub.2NHCH.sub.3, --CH.sub.2N(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2CHCH.sub.2NH.sub.2,
--CH.sub.2CHCH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH(CH.sub.3)NH.sub.2, --CH.sub.2CONH.sub.2, --CH.sub.2OH,
--CH.sub.2CH.sub.2OH, --C(CH.sub.3).sub.2OH,
--CH(OH)CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.2CH.sub.2OH,
--CH.sub.2C(CH.sub.3).sub.2OH, --CH.sub.2CH.sub.2SO.sub.2CH.sub.3,
--CN, --CF.sub.3, --CO.sub.2H, --COCH.sub.3, --CO.sub.2CH.sub.3,
--CO.sub.2C(CH.sub.3).sub.3, --COCH(OH)CH.sub.3, --CONH.sub.2,
--CONHCH.sub.3, --CON(CH.sub.3).sub.2,
--C(CH.sub.3).sub.2CONH.sub.2, --NO.sub.2, --NH.sub.2,
--NHCH.sub.3, --N(CH.sub.3).sub.2, --NHCOCH.sub.3,
--N(CH.sub.3)COCH.sub.1, --NHS(O).sub.2CH.sub.1,
--NHCH.sub.2CH.sub.2NH.sub.2, --NHCH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--N(CH.sub.3)C(CH.sub.3).sub.2CONH.sub.2,
--N(CH.sub.3)CH.sub.2CH.sub.2S(O).sub.2CH.sub.3, .dbd.O, --OH,
--OCH.sub.3, --OCH.sub.2CH.sub.2OCH.sub.3,
--OCH.sub.2CH.sub.2NH.sub.2, --S(O).sub.2N(CH.sub.3).sub.2,
--SCH.sub.3, --CH.sub.2OCH.sub.3, --S(O).sub.2CH.sub.3,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl,
piperidinyl, (piperidin-4-yl)ethyl), pyranyl,
(piperidin-4-ylmethyl), morpholinomethyl, and morpholino; and n is
0, 1, or 2.
8. The compound of claim 1 having the structure of Formula Ia:
##STR00524## where R.sup.4 is selected from F, Cl, Br, I,
--CH.sub.3, --CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2,
--CH.sub.2CH(CH.sub.3).sub.2, --CH.sub.2NH.sub.2,
--CH.sub.2NHCH.sub.3, --CH.sub.2N(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2CHCH.sub.2NH.sub.2,
--CH.sub.2CHCH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH(CH.sub.3)NH.sub.2, --CH.sub.2CONH.sub.2, --CH.sub.2OH,
--CH.sub.2CH.sub.2OH, --C(CH.sub.3).sub.2OH,
--CH(OH)CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.2CH.sub.2OH,
--CH.sub.2C(CH.sub.3).sub.2OH, --CH.sub.2CH.sub.2SO.sub.2CH.sub.3,
--CN, --CF.sub.3, --CO.sub.2H, --COCH.sub.3, --CO.sub.2CH.sub.3,
--CO.sub.2C(CH.sub.3).sub.3, --COCH(OH)CH.sub.3, --CONH.sub.2,
--CONHCH.sub.3, --CON(CH.sub.3).sub.2,
--C(CH.sub.3).sub.2CONH.sub.2, --NO.sub.2, --NH.sub.2,
--NHCH.sub.3, --N(CH.sub.3).sub.2, --NHCOCH.sub.3,
--N(CH.sub.3)COCH.sub.3, --NHS(O).sub.2CH.sub.3,
--NHCH.sub.2CH.sub.2NH.sub.2, --NHCH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--N(CH.sub.3)C(CH.sub.3).sub.2CONH.sub.2,
--N(CH.sub.3)CH.sub.2CH.sub.2S(O).sub.2CH.sub.3, .dbd.O, --OH,
--OCH.sub.3, --OCH.sub.2CH.sub.2OCH.sub.3,
--OCH.sub.2CH.sub.2NH.sub.2, --S(O).sub.2N(CH.sub.3).sub.2,
--SCH.sub.3, --CH.sub.2OCH.sub.3, --S(O).sub.2CH.sub.3,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl,
piperidinyl, (piperidin-4-yl)ethyl), pyranyl,
(piperidin-4-ylmethyl), morpholinomethyl, and morpholino; and n is
0, 1, or 2.
9. The compound of claim 1 having the structure of Formula Ib:
##STR00525## where R.sup.3 is selected from H, C.sub.3-C.sub.12
carbocyclyl, and C.sub.1-C.sub.12 alkyl where carbocyclyl and alkyl
are optionally substituted with F, Cl, CN, --CO.sub.2H,
--COCH.sub.3, --CO.sub.2CH.sub.3, --CO.sub.2C(CH.sub.3).sub.3,
--COCH(OH)CH.sub.3, --CONH.sub.2, --CONHCH.sub.3,
--CON(CH.sub.3).sub.2, --NO.sub.2, --NH.sub.2, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --NHCOCH.sub.3, --N(CH.sub.3)COCH.sub.3,
--NHS(O).sub.2CH.sub.3, --NHCH.sub.2CH.sub.2NH.sub.2,
--NHCH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--N(CH.sub.3)C(CH.sub.3).sub.2CONH.sub.2,
--N(CH.sub.3)CH.sub.2CH.sub.2S(O).sub.2CH.sub.3, .dbd.O, --OH,
--OCH.sub.3, --OCH.sub.2CH.sub.2OCH.sub.3,
--OCH.sub.2CH.sub.2NH.sub.2, --S(O).sub.2N(CH.sub.3).sub.2,
--SCH.sub.3, and --S(O).sub.2CH.sub.3; and n is 0, 1, or 2.
10. The compound of claim 1 having the structure of Formula Ic:
##STR00526## where R.sup.4 is selected from F, Cl, Br, I,
--CH.sub.3, --CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2,
--CH.sub.2CH(CH.sub.3).sub.2, --CH.sub.2NH.sub.2,
--CH.sub.2NHCH.sub.3, --CH.sub.2N(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2CHCH.sub.2NH.sub.2,
--CH.sub.2CHCH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH(CH.sub.3)NH.sub.2, --CH.sub.2CONH.sub.2, --CH.sub.2OH,
--CH.sub.2CH.sub.2OH, --C(CH.sub.3).sub.2OH,
--CH(OH)CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.2CH.sub.2OH,
--CH.sub.2C(CH.sub.3).sub.2OH, --CH.sub.2CH.sub.2SO.sub.2CH.sub.3,
--CN, --CF.sub.3, --CO.sub.2H, --COCH.sub.3, --CO.sub.2CH.sub.3,
--CO.sub.2C(CH.sub.3).sub.3, --COCH(OH)CH.sub.3, --CONH.sub.2,
CONHCH.sub.3, --CON(CH.sub.3).sub.2, --C(CH.sub.3).sub.2CONH.sub.2,
--NO.sub.2, --NH.sub.2, --NHCH.sub.3, --N(CH.sub.3).sub.2,
--NHCOCH.sub.3, --N(CH.sub.3)COCH.sub.3, --NHS(O).sub.2CH.sub.3,
--NHCH.sub.2CH.sub.2NH.sub.2, --NHCH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--N(CH.sub.3)C(CH.sub.3).sub.2CONH.sub.2,
--N(CH.sub.3)CH.sub.2CH.sub.2S(O).sub.2CH.sub.3, .dbd.O, --OH,
--OCH.sub.3, --OCH.sub.2CH.sub.2OCH.sub.3,
--OCH.sub.2CH.sub.2NH.sub.2, --S(O).sub.2N(CH.sub.3).sub.2,
--SCH.sub.3, --CH.sub.2OCH.sub.3, --S(O).sub.2CH.sub.3,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl,
piperidinyl, (piperidin-4-yl)ethyl), pyranyl,
(piperidin-4-ylmethyl), morpholinomethyl, and morpholino; and n is
0, 1, or 2.
11. The compound of claim 1 selected from Table 1 or Table 2.
12. A pharmaceutical composition comprised of a compound of claim 1
and a pharmaceutically acceptable carrier, glidant, diluent, or
excipient.
13. The pharmaceutical composition according to claim 12, further
comprising a second chemotherapeutic agent.
14. A process for making a pharmaceutical composition which
comprises combining a compound of claim 1 with a pharmaceutically
acceptable carrier.
15. A method of treating a disease or disorder which method
comprises administering a therapeutically effective amount of a
compound of claim 1 to a patient with a disease or disorder
selected from cancer, immune disorders, cardiovascular disease,
viral infection, inflammation, metabolism/endocrine function
disorders and neurological disorders, and mediated by Pim
kinase.
16. The method of claim 15 wherein the disease or disorder is
cancer selected from multiple myeloma, breast, ovary, cervix,
prostate, testis, genitourinary tract, esophagus, larynx,
glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung,
epidermoid carcinoma, large cell carcinoma, non-small cell lung
carcinoma (NSCLC), small cell carcinoma, lung adenocarcinoma, bone,
colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular
carcinoma, undifferentiated carcinoma, papillary carcinoma,
seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and
biliary passages, kidney carcinoma, pancreatic, myeloid disorders,
lymphoma, hairy cells, buccal cavity, naso-pharyngeal, pharynx,
lip, tongue, mouth, small intestine, colon-rectum, large intestine,
rectum, brain and central nervous system, Hodgkin's, leukemia,
bronchus, thyroid, liver and intrahepatic bile duct,
hepatocellular, gastric, glioma/glioblastoma, endometrial,
melanoma, kidney and renal pelvis, urinary bladder, uterine corpus,
uterine cervix, acute myelogenous leukemia, chronic myelogenous
leukemia, lymphocytic leukemia, myeloid leukemia, oral cavity and
pharynx, non-Hodgkin lymphoma, melanoma, and villous colon
adenoma.
17. The method of claim 16 further comprising administering an
additional therapeutic agent selected from a chemotherapeutic
agent, an anti-inflammatory agent, an immunomodulatory agent, a
neurotropic factor, an agent for treating cardiovascular disease,
an agent for treating liver disease, an anti-viral agent, an agent
for treating blood disorders, an agent for treating diabetes, and
an agent for treating immunodeficiency disorders.
18. The method of claim 17 wherein the additional therapeutic agent
is selected from dexamethasone, thioTEPA, doxorubicin, vincristine,
rituximab, cyclophosphamide, prednisone, melphalan, lenalidomide,
bortezomib, rapamycin, and cytarabine.
19. A kit for treating a condition mediated by Pim kinase,
comprising: a) a first pharmaceutical composition comprising a
compound of claim 1; and b) instructions for use.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This non-provisional application filed under 37 CFR
.sctn.1.53(b), claims the benefit under 35 USC .sctn.119(e) of U.S.
Provisional Application Ser. No. 61/522,857 filed on 12 Aug. 2011,
which is incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The invention relates generally to pyrazolo[3,4-c]pyridine
compounds for treating disorders mediated by Pim kinase (Pim-1,
Pim-2, and/or Pim-3) inhibitors, thus useful as cancer
therapeutics. The invention also relates to compositions, more
specifically pharmaceutical compositions comprising these compounds
and methods of using the same, either alone or in combination, to
treat various forms of cancer and hyperproliferative disorders, as
well as methods of using the compounds for in vitro, in situ, and
in vivo diagnosis or treatment of mammalian cells, or associated
pathological conditions.
BACKGROUND OF THE INVENTION
[0003] Pim kinases are family of three highly-related serine and
threonine protein kinases encoded by the genes Pim-1, Pim-2, and
Pim-3. The gene names are derived from the phrase Proviral
Insertion, Moloney, frequent integration sites for murine moloney
virus wherein the insertions lead to overexpression of Pim kinases
and either de novo T-cell lymphomas, or dramatic acceleration of
tumorigenesis in a transgenic Myc-driven lymphoma model (Cuypers et
al. (1984) Cell, vol. 37 (1) pp. 141-50; Selten et al. (1985) EMBO
J. vol. 4 (7) pp. 1793-8; van der Lugt et al. (1995) EMBO J. vol.
14 (11) pp. 2536-44; Mikkers et al. (2002) Nature Genetics, vol. 32
(1) pp. 153-9; van Lohuizen et al. (1991) Cell, vol. 65 (5) pp.
737-52). These experiments reveal synergy with the oncogene c-Myc,
and suggest that inhibition of the Pim kinases may have therapeutic
benefit.
[0004] Mouse genetics suggests that antagonizing Pim kinases may
have an acceptable safety profile; a Pim 1-/-; Pim-2-/-,
Pim-3-/-mouse knockout is viable although slightly smaller than
wild type littermates (Mikkers et al. (2004) Mol Cell Biol vol. 24
(13) pp. 6104-154). The three genes give rise to six protein
isoforms including a protein kinase domain, and apparently without
recognizable regulatory domains. All six isoforms are
constitutively active protein kinases that do not require
post-translational modification for activity, thus Pim kinases are
regulated primarily at the transcriptional level (Qian et al.
(2005) J Biol Chem, vol. 280 (7) pp. 6130-7). Pim kinase expression
is highly inducible by cytokines and growth factors receptors and
Pims are direct transcriptional targets of the Stat proteins,
including Stat3 and Stat5. Pim-1, for example, is required for the
130-mediated Stat3 proliferation signal (Aksoy et al. (2007) Stem
Cells, vol. 25 (12) pp. 2996-3004; Hirano et al. (2000) Oncogene
vol. 19 (21) pp. 2548-56; Shirogane et al. (1999) Immunity vol. 11
(6) pp. 709-19).
[0005] Pim kinases function in cellular proliferation and survival
pathways parallel to the PI3k/Akt/mTOR signaling axis (Hammerman et
al. (2005) Blood vol. 105 (11) pp. 4477-83). Indeed, several of the
phosphorylation targets of the PI3k axis including Bad and
cIF4E-BP1 are cell growth and apoptosis regulators and are also
phosphorylation targets of the Pim kinases (Fox et al. (2003) Genes
Dev vol. 17 (15) pp. 1841-54; Macdonald et al. (2006) Cell Biol
vol. 7 pp. 1; Aho et al. (2004) FEBS Letters vol. 571 (1-3) pp.
43-9; Tamburini et al. (2009) Blood vol. 114 (8) pp. 1618-27). Pim
kinase may affect cell survival since phosphorylation of Bad
increases Bcl-2 activity and therefore promotes cell survival.
Likewise, phosphorylation of eIF4E-BP1 by mTOR or Pim kinases
causes depression of eIF4E, promoting mRNA translation and cellular
growth. In addition, Pim-1 has been recognized to promote cell
cycle progression through phosphorylation of CDC25A, p21, and
Cdc25C (Mochizuki et al. (1999) J Biol Chcmvol. 274 (26) pp.
18659-66; Bachmann et al. (2006) Int J Biochem Cell Biol vol. 38
(3) pp. 430-43; Wang et al. (2002) Biochim Biophys Acta vol. 1593
(1) pp. 45-55.
[0006] Pim kinases show synergy in transgenic mouse models with
c-Myc-driven and Akt-driven tumors (Verbeek et al. (1991) Mol Cell
Biol vol. 11 (2) pp. 1176-9; Allen et al. Oncogene (1997) vol. 15
(10) pp. 1133-41; Hammerman et al. (2005) Blood vol. 105 (11) pp.
4477-83). Pim Kinases are involved in transforming activity of
oncogenes identified in acute myeloid leukemia (AML) including
Flt3-ITD, BCR-abl, and Tel-Jak2. Expression of these oncogenes in
BaF3 cells results in upregulation of Pim-1 and Pim-2 expression,
resulting in IL-3 independent growth, and subsequent Pim inhibition
results in apoptosis and cell growth arrest (Adam et al. (2006)
Cancer Research vol. 66 (7) pp. 3828-35). Pim overexpression and
dysregulation has also been noted as a frequent event in many
hematopoietic cancers, including leukemias and lymphoma (Amson et
al. (1989) Proc Natl Acad Sci USA vol. 86 (22) pp. 8857-61); Cohen
et al. (2004) Leuk Lymphoma vol. 45 (5) pp. 951-5; Huttmann et al.
(2006) Leukemia vol. 20 (10) pp. 1774-82) as well as multiple
myeloma (Claudio et al. (2002) Blood vol. 100 (6) pp. 2175-86. Pim
1 has been shown to be overexpressed and correlated to prostate
cancer progression (Cibull et al. (2006) J Clin Pathol vol. 59 (3)
pp. 285-8; Dhanasekaran et al. (2001) Nature vol. 412 (6849) pp.
822-6). Pim 1 expression increases in mouse models with disease
progression (Kim et al. (2002) Proc Natl Acad Sci USA vol. 99 (5)
pp. 2884-9). Pim-1 has been reported to be the most highly
overexpressed mRNA in the subset of human prostate tumor samples
which have a c-Myc-driven gene signature (Ellwood-Yen et al. (2003)
Cancer Cell vol. 4 (3) pp. 223-38). Pim-3 has been also been shown
to be overexpressed and to have a functional role in pancreatic
cancer and hepatocellular carcinoma (Li et al. (2006) Cancer
Research vol. 66 (13) pp. 6741-7; Fujii et al. (2005) Int. J
Cancer, vol. 114 (2) pp. 209-18).
[0007] Beyond oncology therapeutic and diagnostic applications, Pim
kinases could play an important role in normal immune system
function and Pim inhibition could be therapeutic for a number of
different immunologic pathologies including inflammation,
autoimmune conditions, allergy, and immune suppression for organ
transplantation (Aho et al. Expression of human Pim family genes is
selectively up-regulated by cytokines promoting T helper type 1,
but not T helper type 2, cell differentiation. Immunology (2005)
vol. 116 (1) pp. 82-8).
SUMMARY OF THE INVENTION
[0008] The invention relates to pyrazolo[3,4-c]pyridine compounds
for treating disorders mediated by Pim kinase (Pim-1, Pim-2, and/or
Pim-3) inhibitors Formula I compounds.
[0009] Formula I compounds have the structure:
##STR00002##
[0010] and stereoisomers, geometric isomers, tautomers, and
pharmaceutically acceptable salts thereof. The various
substituents, including R.sup.1 and R.sup.2 are as defined
herein.
[0011] One aspect of the invention is a pharmaceutical composition
comprised of a Formula I compound and a pharmaceutically acceptable
carrier, glidant, diluent, or excipient. The pharmaceutical
composition may further comprise a second chemotherapeutic
agent.
[0012] Another aspect of the invention is a process for making a
pharmaceutical composition which comprises combining a Formula I
compound with a pharmaceutically acceptable carrier.
[0013] The invention includes a method of treating a disease or
disorder which method comprises administering a therapeutically
effective amount of a Formula I compound to a patient with a
disease or disorder selected from cancer, immune disorders,
cardiovascular disease, viral infection, inflammation,
metabolism/endocrine function disorders and neurological disorders,
and mediated by Pim kinase. The method includes further
administering an additional therapeutic agent selected from a
chemotherapeutic agent, an anti-inflammatory agent, an
immunomodulatory agent, a neurotropic factor, an agent for treating
cardiovascular disease, an agent for treating liver disease, an
anti-viral agent, an agent for treating blood disorders, an agent
for treating diabetes, and an agent for treating immunodeficiency
disorders.
[0014] The invention includes a kit for treating a condition
mediated by Pim kinase, comprising: a) a first pharmaceutical
composition comprising a Formula I compound; and b) instructions
for use.
[0015] The invention includes a Formula I compound for use as a
medicament, and for use in treating a disease or disorder selected
from cancer, immune disorders, cardiovascular disease, viral
infection, inflammation, metabolism/endocrine function disorders
and neurological disorders, and mediated by Pim kinase.
[0016] The invention includes use of a Formula I compound in the
manufacture of a medicament for the treatment of cancer, immune
disorders, cardiovascular disease, viral infection, inflammation,
metabolism/endocrine function disorders and neurological disorders,
and where the medicament mediates Pim kinase.
[0017] The invention includes methods of making a Formula I
compound.
DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS
[0018] Reference will now be made in detail to certain embodiments
of the invention, examples of which are illustrated in the
accompanying structures and formulas. While the invention will be
described in conjunction with the enumerated embodiments, it will
be understood that they are not intended to limit the invention to
those embodiments. On the contrary, the invention is intended to
cover all alternatives, modifications, and equivalents which may be
included within the scope of the present invention as defined by
the claims. One skilled in the art will recognize many methods and
materials similar or equivalent to those described herein, which
could be used in the practice of the present invention. The present
invention is in no way limited to the methods and materials
described. In the event that one or more of the incorporated
literature, patents, and similar materials differs from or
contradicts this application, including but not limited to defined
terms, term usage, described techniques, or the like, this
application controls.
DEFINITIONS
[0019] The term "alkyl" as used herein refers to a saturated linear
or branched-chain monovalent hydrocarbon radical of one to twelve
carbon atoms (C.sub.1-C.sub.12), wherein the alkyl radical may be
optionally substituted independently with one or more substituents
described below. In another embodiment, an alkyl radical is one to
eight carbon atoms (C.sub.1-C.sub.8), or one to six carbon atoms
(C.sub.1-C.sub.6). Examples of alkyl groups include, but are not
limited to, methyl (Me, --CH.sub.3), ethyl (Et,
--CH.sub.2CH.sub.3), 1-propyl (n-Pr, n-propyl,
--CH.sub.2CH.sub.2CH.sub.3), 2-propyl (i-Pr, i-propyl,
--CH(CH.sub.3).sub.2), 1-butyl (n-Bu, n-butyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-methyl-1-propyl (i-Bu,
i-butyl, --CH.sub.2CH(CH.sub.3).sub.2), 2-butyl (s-Bu, s-butyl,
--CH(CH.sub.3)CH.sub.2CH.sub.3), 2-methyl-2-propyl (t-Bu, t-butyl,
--C(CH.sub.3).sub.3), 1-pentyl (n-pentyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-pentyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3), 3-pentyl
(--CH(CH.sub.2CH.sub.3).sub.2), 2-methyl-2-butyl
(--C(CH.sub.3).sub.2CH.sub.2CH.sub.3), 3-methyl-2-butyl
(--CH(CH.sub.3)CH(CH.sub.3).sub.2), 3-methyl-1-butyl
(--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2), 2-methyl-1-butyl
(--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3), 1-hexyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-hexyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3-hexyl
(--CH(CH.sub.2CH.sub.3)(CH.sub.2CH.sub.2CH.sub.3)),
2-methyl-2-pentyl (--C(CH.sub.3).sub.2CH.sub.2CH.sub.2CH.sub.3),
3-methyl-2-pentyl (--CH(CH.sub.3)CH(CH.sub.3)CH.sub.2CH.sub.3),
4-methyl-2-pentyl (--CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2),
3-methyl-3-pentyl (--C(CH.sub.3)(CH.sub.2CH.sub.3).sub.2),
2-methyl-3-pentyl (--CH(CH.sub.2CH.sub.3)CH(CH.sub.3).sub.2),
2,3-dimethyl-2-butyl (--C(CH.sub.3).sub.2CH(CH.sub.3).sub.2),
3,3-dimethyl-2-butyl (--CH(CH.sub.3)C(CH.sub.3).sub.3, 1-heptyl,
1-octyl, and the like.
[0020] The term "alkylene" as used herein refers to a saturated
linear or branched-chain divalent hydrocarbon radical of one to
twelve carbon atoms (C.sub.1-C.sub.12), wherein the alkylene
radical may be optionally substituted independently with one or
more substituents described below. In another embodiment, an
alkylene radical is one to eight carbon atoms (C.sub.1-C.sub.8), or
one to six carbon atoms (C.sub.1-C.sub.6). Examples of alkylene
groups include, but are not limited to, methylene (--CH.sub.2--),
ethylene (--CH.sub.2CH.sub.2--), propylene
(--CH.sub.2CH.sub.2CH.sub.2--), and the like.
[0021] The term "alkenyl" refers to linear or branched-chain
monovalent hydrocarbon radical of two to eight carbon atoms
(C.sub.2-C.sub.8) with at least one site of unsaturation, i.e., a
carbon-carbon, sp.sup.2 double bond, wherein the alkenyl radical
may be optionally substituted independently with one or more
substituents described herein, and includes radicals having "cis"
and "trans" orientations, or alternatively, "E" and "Z"
orientations. Examples include, but are not limited to, ethylenyl
or vinyl (--CH.dbd.CH.sub.2), allyl (--CH.sub.2CH.dbd.CH.sub.2),
and the like.
[0022] The term "alkenylene" refers to linear or branched-chain
divalent hydrocarbon radical of two to eight carbon atoms
(C.sub.2-C.sub.8) with at least one site of unsaturation, i.e., a
carbon-carbon, sp.sup.2 double bond, wherein the alkenylene radical
may be optionally and independently substituted with one or more
substituents described herein, and includes radicals having "cis"
and "trans" orientations, or alternatively, "E" and "Z"
orientations. Examples include, but are not limited to,
ethylenylene or vinylene (--CH.dbd.CH--), allyl
(--CH.sub.2CH.dbd.CH--), and the like.
[0023] The term "alkynyl" refers to a linear or branched monovalent
hydrocarbon radical of two to eight carbon atoms (C.sub.2-C.sub.8)
with at least one site of unsaturation, i.e., a carbon-carbon, sp
triple bond, wherein the alkynyl radical may be optionally
substituted independently with one or more substituents described
herein. Examples include, but are not limited to, ethynyl
(--C.ident.CH), propynyl (propargyl, --CH.sub.2C.ident.CH), and the
like.
[0024] The term "alkynylene" refers to a linear or branched
divalent hydrocarbon radical of two to eight carbon atoms
(C.sub.2-C.sub.8) with at least one site of unsaturation, i.e., a
carbon-carbon, sp triple bond, wherein the alkynylene radical may
be optionally substituted independently with one or more
substituents described herein. Examples include, but are not
limited to, ethynylene (--C.ident.C--), propynylene (propargylene,
--CH.sub.2C.ident.C--), and the like.
[0025] The terms "carbocycle", "carbocyclyl", "carbocyclic ring"
and "cycloalkyl" refer to a monovalent non-aromatic, saturated or
partially unsaturated ring having 3 to 12 carbon atoms
(C.sub.3-C.sub.12) as a monocyclic ring or 7 to 12 carbon atoms as
a bicyclic ring. Bicyclic carbocycles having 7 to 12 atoms can be
arranged, for example, as a bicyclo[4,5], [5,5], [5,6] or [6,6]
system, and bicyclic carbocycles having 9 or 10 ring atoms can be
arranged as a bicyclo[5,6] or [6,6] system, or as bridged systems
such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and
bicyclo[3.2.2]nonane. Spiro moieties are also included within the
scope of this definition. Examples of monocyclic carbocycles
include, but are not limited to, cyclopropyl, cyclobutyl,
cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl,
1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl,
1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl,
cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and
the like. Carbocyclyl groups are optionally substituted
independently with one or more substituents described herein.
[0026] "Aryl" means a monovalent aromatic hydrocarbon radical of
6-20 carbon atoms (C.sub.6-C.sub.20) derived by the removal of one
hydrogen atom from a single carbon atom of a parent aromatic ring
system. Some aryl groups are represented in the exemplary
structures as "Ar". Aryl includes bicyclic radicals comprising an
aromatic ring fused to a saturated, partially unsaturated ring, or
aromatic carbocyclic ring. Typical aryl groups include, but are not
limited to, radicals derived from benzene (phenyl), substituted
benzenes, naphthalene, anthracene, biphenyl, indenyl, indanyl,
1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the like.
Aryl groups are optionally substituted independently with one or
more substituents described herein.
[0027] "Arylene" means a divalent aromatic hydrocarbon radical of
6-20 carbon atoms (C.sub.6-C.sub.20) derived by the removal of two
hydrogen atom from a two carbon atoms of a parent aromatic ring
system. Some arylene groups are represented in the exemplary
structures as "Ar". Arylene includes bicyclic radicals comprising
an aromatic ring fused to a saturated, partially unsaturated ring,
or aromatic carbocyclic ring. Typical arylene groups include, but
are not limited to, radicals derived from benzene (phenylene),
substituted benzenes, naphthalene, anthracene, biphenylene,
indenylene, indanylene, 1,2-dihydronaphthalene,
1,2,3,4-tetrahydronaphthyl, and the like. Arylene groups are
optionally substituted with one or more substituents described
herein.
[0028] The terms "heterocycle," "heterocyclyl" and "heterocyclic
ring" are used interchangeably herein and refer to a saturated or a
partially unsaturated (i.e., having one or more double and/or
triple bonds within the ring) carbocyclic radical of 3 to about 20
ring atoms in which at least one ring atom is a heteroatom selected
from nitrogen, oxygen, phosphorus and sulfur, the remaining ring
atoms being C, where one or more ring atoms is optionally
substituted independently with one or more substituents described
below. A heterocycle may be a monocycle having 3 to 7 ring members
(2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P,
and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon
atoms and 1 to 6 heteroatoms selected from N, O, P, and S), for
example: a bicyclo[4,5], [5,5], [5,6], or [6,6] system.
Heterocycles are described in Paquette, Leo A.; "Principles of
Modern Heterocyclic Chemistry" (W. A. Benjamin, New York, 1968),
particularly Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of
Heterocyclic Compounds, A series of Monographs" (John Wiley &
Sons, New York, 1950 to present), in particular Volumes 13, 14, 16,
19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. "Heterocyclyl"
also includes radicals where heterocycle radicals are fused with a
saturated, partially unsaturated ring, or aromatic carbocyclic or
heterocyclic ring. Examples of heterocyclic rings include, but are
not limited to, morpholin-4-yl, piperidin-1-yl, piperazinyl,
piperazin-4-yl-2-one, piperazin-4-yl-3-one, pyrrolidin-1-yl,
thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl, azocan-1-yl,
azetidin-1-yl, octahydropyrido[1,2-a]pyrazin-2-yl,
[1,4]diazepan-1-yl, pyrrolidinyl, tetrahydrofuranyl,
dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,
dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino,
thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl,
azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl,
thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl,
3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,
1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl,
dihydropyranyl, dihydrothienyl, dihydrofuranyl,
pyrazolidinylimidazolinyl, imidazolidinyl,
3-azabicyco[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,
azabicyclo[2.2.2]hexanyl, 3H-indolyl quinolizinyl and N-pyridyl
ureas. Spiro moieties are also included within the scope of this
definition. Examples of a heterocyclic group wherein 2 ring atoms
are substituted with oxo (.dbd.O) moieties are pyrimidinonyl and
1,1-dioxo-thiomorpholinyl. The heterocycle groups herein are
optionally substituted independently with one or more substituents
described herein.
[0029] The term "heteroaryl" refers to a monovalent aromatic
radical of 5-, 6-, or 7-membered rings, and includes fused ring
systems (at least one of which is aromatic) of 5-20 atoms,
containing one or more heteroatoms independently selected from
nitrogen, oxygen, and sulfur. Examples of heteroaryl groups are
pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl,
imidazopyridinyl, pyrimidinyl (including, for example,
4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,
furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl,
isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl,
tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,
cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,
triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl,
thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl,
benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl,
quinoxalinyl, naphthyridinyl, and furopyridinyl. Heteroaryl groups
are optionally substituted independently with one or more
substituents described herein.
[0030] The heterocycle or heteroaryl groups may be carbon
(carbon-linked), or nitrogen (nitrogen-linked) bonded where such is
possible. By way of example and not limitation, carbon bonded
heterocycles or heteroaryls are bonded at position 2, 3, 4, 5, or 6
of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2,
4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine,
position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran,
thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an
oxazole, imidazole or thiazole, position 3, 4, or 5 of an
isoxazole, pyrazole, or isothiazole, position 2 or 3 of an
aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4,
5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of
an isoquinoline.
[0031] By way of example and not limitation, nitrogen bonded
heterocycles or heteroaryls are bonded at position 1 of an
aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline,
3-pyrroline, imidazole, imidazolidine, 2-imidazoline,
3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,
piperidine, piperazine, indole, indoline, 1H-indazole, position 2
of a isoindole, or isoindoline, position 4 of a morpholine, and
position 9 of a carbazole, or .beta.-carboline.
[0032] The terms "treat" and "treatment" refer to both therapeutic
treatment and prophylactic or preventative measures, wherein the
object is to prevent or slow down (lessen) an undesired
physiological change or disorder, such as the development or spread
of cancer. For purposes of this invention, beneficial or desired
clinical results include, but are not limited to, alleviation of
symptoms, diminishment of extent of disease, stabilized (i.e., not
worsening) state of disease, delay or slowing of disease
progression, amelioration or palliation of the disease state, and
remission (whether partial or total), whether detectable or
undetectable. "Treatment" can also mean prolonging survival as
compared to expected survival if not receiving treatment. Those in
need of treatment include those already with the condition or
disorder as well as those prone to have the condition or disorder
or those in which the condition or disorder is to be prevented.
[0033] The phrase "therapeutically effective amount" means an
amount of a compound of the present invention that (i) treats or
prevents the particular disease, condition, or disorder, (ii)
attenuates, ameliorates, or eliminates one or more symptoms of the
particular disease, condition, or disorder, or (iii) prevents or
delays the onset of one or more symptoms of the particular disease,
condition, or disorder described herein. In the case of cancer, the
therapeutically effective amount of the drug may reduce the number
of cancer cells; reduce the tumor size; inhibit (i.e., slow to some
extent and preferably stop) cancer cell infiltration into
peripheral organs; inhibit (i.e., slow to some extent and
preferably stop) tumor metastasis; inhibit, to some extent, tumor
growth; and/or relieve to some extent one or more of the symptoms
associated with the cancer. To the extent the drug may prevent
growth and/or kill existing cancer cells, it may be cytostatic
and/or cytotoxic. For cancer therapy, efficacy can be measured, for
example, by assessing the time to disease progression (TTP) and/or
determining the response rate (RR).
[0034] The terms "cancer" refers to or describe the physiological
condition in mammals that is typically characterized by unregulated
cell growth. A "tumor" comprises one or more cancerous cells.
Examples of cancer include, but are not limited to, carcinoma,
lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies.
More particular examples of such cancers include squamous cell
cancer (e.g., epithelial squamous cell cancer), lung cancer
including small-cell lung cancer, non-small cell lung cancer
("NSCLC"), adenocarcinoma of the lung and squamous carcinoma of the
lung, cancer of the peritoneum, hepatocellular cancer, gastric or
stomach cancer including gastrointestinal cancer, pancreatic
cancer, glioblastoma, cervical cancer, ovarian cancer, liver
cancer, bladder cancer, hepatoma, breast cancer, colon cancer,
rectal cancer, colorectal cancer, endometrial or uterine carcinoma,
salivary gland carcinoma, kidney or renal cancer, prostate cancer,
vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma,
penile carcinoma, as well as head and neck cancer.
[0035] A "chemotherapeutic agent" is a chemical compound useful in
the treatment of cancer, regardless of mechanism of action. Classes
of chemotherapeutic agents include, but are not limited to:
alkylating agents, antimetabolites, spindle poison plant alkaloids,
cytotoxic/antitumor antibiotics, topoisomerase inhibitors,
antibodies, photosensitizers, and kinase inhibitors.
Chemotherapeutic agents include compounds used in "targeted
therapy" and conventional chemotherapy. Examples of
chemotherapeutic agents include: erlotinib (TARCEVA.RTM.,
Genentech/OSI Pharm.), docetaxel (TAXOTERE.RTM., Sanofi-Aventis),
5-FU (fluorouracil, 5-fluorouracil, CAS No. 51-21-8), gemcitabine
(GEMZAR.RTM., Lilly), PD-0325901 (CAS No. 391210-10-9, Pfizer),
cisplatin (cis-diamine, dichloroplatinum(II), CAS No. 15663-27-1),
carboplatin (CAS No. 41575-94-4), paclitaxel (TAXOL.RTM.,
Bristol-Myers Squibb Oncology, Princeton, N.J.), trastuzumab
(HERCEPTIN.RTM., Genentech), temozolomide
(4-methyl-5-oxo-2,3,4,6,8-pentazabicyclo[4.3.0]nona-2,7,9-triene-9-carbox-
amide, CAS No. 85622-93-1, TEMODAR.RTM., TEMODAL.RTM., Schering
Plough), tamoxifen
((Z)-2-[4-(1,2-diphenylbut-1-enyl)phenoxy]-N,N-dimethylethanami-
ne, NOLVADEX.RTM., ISTUBAL.RTM., VALODEX.RTM.)), and doxorubicin
(ADRIAMYCIN.RTM.)), Akti-1/2, HPPD, and rapamycin.
[0036] More examples of chemotherapeutic agents include:
oxaliplatin (ELOXATIN.RTM., Sanofi), bortezomib (VELCADE.RTM.,
Millennium Pharm.), sutent (SUNITINIB.RTM., SU11248, Pfizer),
letrozole (FEMARA.RTM., Novartis), imatinib mesylate (GLEEVEC.RTM.,
Novartis), XL-518 (Mek inhibitor, Exelixis, WO 2007/044515),
ARRY-886 (Mek inhibitor, AZD6244, Array BioPharma, Astra Zeneca),
SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K
inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787/ZK
222584 (Novartis), fulvestrant (FASLODEX.RTM., AstraZeneca),
leucovorin (folinic acid), rapamycin (sirolimus, RAPAMUNE.RTM.,
Wyeth), everolimus (AFINITOR.RTM., Novartis), lapatinib
(TYKERB.RTM., GSK572016, Glaxo Smith Kline), lonafarnib
(SARASAR.TM., SCH 66336, Schering Plough), sorafenib (NEXAVAR.RTM.,
BAY43-9006, Bayer Labs), gefitinib (IRESSA.RTM., AstraZeneca),
irinotecan (CAMPTOSAR.RTM., CPT-11, Pfizer), tipifarnib
(ZARNESTRA.TM., Johnson & Johnson), ABRAXANE.TM.
(Cremophor-free), albumin-engineered nanoparticle formulations of
paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.),
vandetanib (rINN, ZD6474, ZACTIMA.RTM., AstraZeneca),
chloranmbucil, AG1478, AG1571 (SU 5271; Sugen), temsirolimus
(TORISEL.RTM., Wyeth), pazopanib (GlaxoSmithKline), canfosfamide
(TELCYTA.RTM., Telik), abiraterone (ZYTIGA.RTM., Johnson &
Johnson), thiotepa and cyclosphosphamide (CYTOXAN.RTM.,
NEOSAR.RTM.); alkyl sulfonates such as busulfan, improsulfan and
piposulfan; aziridines such as benzodopa, carboquone, meturedopa,
and uredopa; ethylenimines and methylamelamines including
altretamine, triethylenemelamine, triethylenephosphoramide,
triethylenethiophosphoramide and trimethylomelamine; acetogenins
(especially bullatacin and bullatacinone); a camptothecin
(including the synthetic analog topotecan); bryostatin;
callystatin; CC-1065 (including its adozelesin, carzelesin and
bizelesin synthetic analogs); cryptophycins (particularly
cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin
(including the synthetic analogs, KW-2189 and CB1-TM1);
eleutherobin; pancratistatin; a sarcodictyin; spongistatin;
nitrogen mustards such as chlorambucil, chlornaphazine,
chlorophosphamide, estramustine, ifosfamide, mechlorethamine,
mechlorethamine oxide hydrochloride, melphalan, novembichin,
phenesterine, prednimustine, trofosfamide, uracil mustard;
nitrosoureas such as carmustine, chlorozotocin, fotemustine,
lomustine, nimustine, and ranimnustine; antibiotics such as the
enediyne antibiotics (e.g., calicheamicin, calicheamicin gamma1I,
calicheamicin omegaI1 (Angew Chem. Intl. Ed. Engl. (1994)
33:183-186); dynemicin, dynemicin A; bisphosphonates, such as
clodronate; an esperamicin; as well as neocarzinostatin chromophore
and related chromoprotein enediyne antibiotic chromophores),
aclacinomysins, actinomycin, authramycin, azaserine, bleomycins,
cactinomycin, carabicin, carminomycin, carzinophilin,
chromomycinis, dactinomycin, daunorubicin, detorubicin,
6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin,
cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and
deoxydoxorubicin), epirubicin, esorubicin, idarubicin, nemorubicin,
marcellomycin, mitomycins such as mitomycin C, mycophenolic acid,
nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin,
quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,
ubenimex, zinostatin, zorubicin; anti-metabolites such as
methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as
denopterin, methotrexate, pteropterin, trimetrexate; purine analogs
such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine;
pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine,
carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine,
floxuridine; androgens such as calusterone, dromostanolone
propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals
such as aminoglutethimide, mitotane, trilostane; folic acid
replenisher such as frolinic acid; aceglatone; aldophosphamide
glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil;
bisantrene; edatraxate; defofamine; demecolcine; diaziquone;
elformithine; elliptinium acetate; an epothilone; etoglucid;
gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids
such as maytansine and ansamitocins; mitoguazone; mitoxantrone;
mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin;
losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine;
PSK.RTM. polysaccharide complex (JHS Natural Products, Eugene,
Oreg.); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic
acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes
(especially T-2 toxin, verracurin A, roridin A and anguidine);
urethan; vindesine; dacarbazine; mannomustine; mitobronitol;
mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C");
cyclophosphamide; thiotepa; 6-thioguanine; mercaptopurine;
methotrexate; platinum analogs such as cisplatin and carboplatin;
vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone;
vincristine; vinorelbine (NAVELBINE.RTM.); novantrone; teniposide;
edatrexate; daunomycin; aminopterin; capecitabine (XELODA.RTM.,
Roche); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000;
difluoromethylornithine (DMFO); retinoids such as retinoic acid;
and pharmaceutically acceptable salts, acids and derivatives of any
of the above.
[0037] Examples of chemotherapeutic agents also include:
dexamethasone, thioTEPA, doxorubicin, vincristine, rituximab,
cyclophosphamide, prednisone, melphalan, lenalidomide, bortezomib,
rapamycin, and cytarabine.
[0038] Also included in the definition of "chemotherapeutic agent"
are: (i) anti-hormonal agents that act to regulate or inhibit
hormone action on tumors such as anti-estrogens and selective
estrogen receptor modulators (SERMs), including, for example,
tamoxifen (including NOLVADEX.RTM.; tamoxifen citrate), raloxifene,
droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018,
onapristone, and FARESTON.RTM. (toremifine citrate); (ii) aromatase
inhibitors that inhibit the enzyme aromatase, which regulates
estrogen production in the adrenal glands, such as, for example,
4(5)-imidazoles, aminoglutethimide, MEGASE.RTM. (megestrol
acetate), AROMASIN.RTM. (exemestane; Pfizer), formestanie,
fadrozole, RIVISOR.RTM. (vorozole), FEMARA.RTM. (letrozole;
Novartis), and ARIMIDEX.RTM. (anastrozole; AstraZeneca); (iii)
anti-androgens such as flutamide, nilutamide, bicalutamide,
leuprolide, and goserelin; as well as troxacitabine (a
1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase
inhibitors such as MEK inhibitors (WO 2007/044515); (v) lipid
kinase inhibitors; (vi) antisense oligonucleotides, particularly
those which inhibit expression of genes in signaling pathways
implicated in aberrant cell proliferation, for example, PKC-alpha,
Raf and H-Ras, such as oblimersen (GENASENSE.RTM., Genta Inc.);
(vii) ribozymes such as VEGF expression inhibitors (e.g.,
ANGIOZYME.RTM.) and HER2 expression inhibitors; (viii) vaccines
such as gene therapy vaccines, for example, ALLOVECTIN.RTM.,
LEUVECTIN.RTM., and VAXID.RTM.; PROLEUKIN.RTM. rIL-2; topoisomerase
1 inhibitors such as LURTOTECAN.RTM.; ABARELIX.RTM. rmRH; (ix)
anti-angiogenic agents such as bevacizumab (AVASTIN.RTM.,
Genentech); and pharmaceutically acceptable salts, acids and
derivatives of any of the above.
[0039] Also included in the definition of "chemotherapeutic agent"
are therapeutic antibodies such as alemtuzumab (Campath),
bevacizumab (AVASTIN.RTM., Genentech); cetuximab (ERBITUX.RTM.,
Imclone); panitumumab (VECTIBIX.RTM., Amgen), rituximab
(RITUXAN.RTM., Genentech/Biogen Idec), pertuzumab (OMNITARG.TM.,
2C4, Genentech), trastuzumab (HERCEPTIN.RTM., Genentech),
tositumomab (Bexxar, Corixia), and the antibody drug conjugate,
gemtuzumab ozogamicin (MYLOTARG.RTM., Wyeth).
[0040] Humanized monoclonal antibodies with therapeutic potential
as chemotherapeutic agents in combination with the PI3K inhibitors
of the invention include: alemtuzumab, apolizumab, aselizumab,
atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine,
cantuzumab mertansine, cedelizumab, certolizumab pegol,
cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab,
epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab
ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab,
lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab,
natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab,
omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab,
pertuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab,
reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab,
siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab,
talizumab, tefibazumab, tocilizumab, toralizumab, trastuzumab,
tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab,
and visilizumab.
[0041] A "metabolite" is a product produced through metabolism in
the body of a specified compound or salt thereof. Metabolites of a
compound may be identified using routine techniques known in the
art and their activities determined using tests such as those
described herein. Such products may result for example from the
oxidation, reduction, hydrolysis, amidation, deamidation,
esterification, deesterification, enzymatic cleavage, and the like,
of the administered compound. Accordingly, the invention includes
metabolites of compounds of the invention, including compounds
produced by a process comprising contacting a Formula I compound of
this invention with a mammal for a period of time sufficient to
yield a metabolic product thereof.
[0042] The term "package insert" is used to refer to instructions
customarily included in commercial packages of therapeutic
products, that contain information about the indications, usage,
dosage, administration, contraindications and/or warnings
concerning the use of such therapeutic products.
[0043] The term "chiral" refers to molecules which have the
property of non-superimposability of the mirror image partner,
while the term "achiral" refers to molecules which are
superimposable on their mirror image partner.
[0044] The term "stereoisomers" refers to compounds which have
identical chemical constitution, but differ with regard to the
arrangement of the atoms or groups in space.
[0045] "Diastereomer" refers to a stereoisomer with two or more
centers of chirality and whose molecules are not mirror images of
one another. Diastereomers have different physical properties, e.g.
melting points, boiling points, spectral properties, and
reactivities. Mixtures of diastereomers may separate under high
resolution analytical procedures such as electrophoresis and
chromatography.
[0046] "Enantiomers" refer to two stereoisomers of a compound which
are non-superimposable mirror images of one another.
[0047] Stereochemical definitions and conventions used herein
generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of
Chemical Terms (1984) McGraw-Hill Book Company, New York; and
Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds",
John Wiley & Sons, Inc., New York, 1994. The compounds of the
invention may contain asymmetric or chiral centers, and therefore
exist in different stereoisomeric forms. It is intended that all
stereoisomeric forms of the compounds of the invention, including
but not limited to, diastereomers, enantiomers and atropisomers, as
well as mixtures thereof such as racemic mixtures, form part of the
present invention. Many organic compounds exist in optically active
forms, i.e., they have the ability to rotate the plane of
plane-polarized light. In describing an optically active compound,
the prefixes D and L, or R and S, are used to denote the absolute
configuration of the molecule about its chiral center(s). The
prefixes d and 1 or (+) and (-) are employed to designate the sign
of rotation of plane-polarized light by the compound, with (-) or 1
meaning that the compound is levorotatory. A compound prefixed with
(+) or d is dextrorotatory. For a given chemical structure, these
stereoisomers are identical except that they are mirror images of
one another. A specific stereoisomer may also be referred to as an
enantiomer, and a mixture of such isomers is often called an
enantiomeric mixture. A 50:50 mixture of enantiomers is referred to
as a racemic mixture or a racemate, which may occur where there has
been no stereoselection or stereospecificity in a chemical reaction
or process. The terms "racemic mixture" and "racemate" refer to an
equimolar mixture of two enantiomeric species, devoid of optical
activity.
[0048] The term "tautomer" or "tautomeric form" refers to
structural isomers of different energies which are interconvertible
via a low energy barrier. For example, proton tautomers (also known
as prototropic tautomers) include interconversions via migration of
a proton, such as keto-enol and imine-enamine isomerizations.
Valence tautomers include interconversions by reorganization of
some of the bonding electrons.
[0049] The phrase "pharmaceutically acceptable salt" as used
herein, refers to pharmaceutically acceptable organic or inorganic
salts of a compound of the invention. Exemplary salts include, but
are not limited, to sulfate, citrate, acetate, oxalate, chloride,
bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate,
isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate,
tannate, pantothenate, bitartrate, ascorbate, succinate, maleate,
gentisinate, fumarate, gluconate, glucuronate, saccharate, formate,
benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate,
benzenesulfonate, p-toluenesulfonate, and pamoate (i.e.,
1,1'-methylene-bis(2-hydroxy-3-naphthoate)) salts. A
pharmaceutically acceptable salt may involve the inclusion of
another molecule such as an acetate ion, a succinate ion or other
counter ion. The counter ion may be any organic or inorganic moiety
that stabilizes the charge on the parent compound. Furthermore, a
pharmaceutically acceptable salt may have more than one charged
atom in its structure. Instances where multiple charged atoms are
part of the pharmaceutically acceptable salt can have multiple
counter ions. Hence, a pharmaceutically acceptable salt can have
one or more charged atoms and/or one or more counter ion.
[0050] If the compound of the invention is a base, the desired
pharmaceutically acceptable salt may be prepared by any suitable
method available in the art, for example, treatment of the free
base with an inorganic acid, such as hydrochloric acid, hydrobromic
acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric
acid and the like, or with an organic acid, such as acetic acid,
trifluoroacetic acid, maleic acid, succinic acid, mandelic acid,
fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic
acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid
or galacturonic acid, an alpha hydroxy acid, such as citric acid or
tartaric acid, an amino acid, such as aspartic acid or glutamic
acid, an aromatic acid, such as benzoic acid or cinnamic acid, a
sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic
acid, or the like.
[0051] If the compound of the invention is an acid, the desired
pharmaceutically acceptable salt may be prepared by any suitable
method, for example, treatment of the free acid with an inorganic
or organic base, such as an amine (primary, secondary or tertiary),
an alkali metal hydroxide or alkaline earth metal hydroxide, or the
like. Illustrative examples of suitable salts include, but are not
limited to, organic salts derived from amino acids, such as glycine
and arginine, ammonia, primary, secondary, and tertiary amines, and
cyclic amines, such as piperidine, morpholine and piperazine, and
inorganic salts derived from sodium, calcium, potassium, magnesium,
manganese, iron, copper, zinc, aluminum and lithium.
[0052] The phrase "pharmaceutically acceptable" indicates that the
substance or composition must be compatible chemically and/or
toxicologically, with the other ingredients comprising a
formulation, and/or the mammal being treated therewith.
[0053] A "solvate" refers to an association or complex of one or
more solvent molecules and a compound of the invention. Examples of
solvents that form solvates include, but are not limited to, water,
isopropanol, ethanol, methanol, DMSO, ethylacetate, acetic acid,
and ethanolamine.
[0054] The terms "compound of this invention," and "compounds of
the present invention" and "compounds of Formula I" include
compounds of Formulas I and stereoisomers, geometric isomers,
tautomers, solvates, metabolites, and pharmaceutically acceptable
salts and prodrugs thereof.
[0055] Any formula or structure given herein, including Formula I
compounds, is also intended to represent hydrates, solvates, and
polymorphs of such compounds, and mixtures thereof.
[0056] Any formula or structure given herein, including Formula I
compounds, is also intended to represent unlabeled forms as well as
isotopically labeled forms of the compounds. Isotopically labeled
compounds have structures depicted by the formulas given herein
except that one or more atoms are replaced by an atom having a
selected atomic mass or mass number. Examples of isotopes that can
be incorporated into compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and
chlorine, such as, but not limited to 2H (deuterium, D), 3H
(tritium), 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl, and 125I.
Various isotopically labeled compounds of the present invention,
for example those into which radioactive isotopes such as 3H, 13C,
and 14C are incorporated. Such isotopically labelled compounds may
be useful in metabolic studies, reaction kinetic studies, detection
or imaging techniques, such as positron emission tomography (PET)
or single-photon emission computed tomography (SPECT) including
drug or substrate tissue distribution assays, or in radioactive
treatment of patients. Deuterium labelled or substituted
therapeutic compounds of the invention may have improved DMPK (drug
metabolism and pharmacokinetics) properties, relating to
distribution, metabolism, and excretion (ADME). Substitution with
heavier isotopes such as deuterium may afford certain therapeutic
advantages resulting from greater metabolic stability, for example
increased in vivo half-life or reduced dosage requirements. An 18F
labeled compound may be useful for PET or SPECT studies.
Isotopically labeled compounds of this invention and prodrugs
thereof can generally be prepared by carrying out the procedures
disclosed in the schemes or in the examples and preparations
described below by substituting a readily available isotopically
labeled reagent for a non-isotopically labeled reagent. Further,
substitution with heavier isotopes, particularly deuterium (i.e.,
2H or D) may afford certain therapeutic advantages resulting from
greater metabolic stability, for example increased in vivo
half-life or reduced dosage requirements or an improvement in
therapeutic index. It is understood that deuterium in this context
is regarded as a substituent in the compound of the formula (I).
The concentration of such a heavier isotope, specifically
deuterium, may be defined by an isotopic enrichment factor. In the
compounds of this invention any atom not specifically designated as
a particular isotope is meant to represent any stable isotope of
that atom. Unless otherwise stated, when a position is designated
specifically as "H" or "hydrogen", the position is understood to
have hydrogen at its natural abundance isotopic composition.
Accordingly, in the compounds of this invention any atom
specifically designated as a deuterium (D) is meant to represent
deuterium.
PYRAZOLO[3,4-C]PYRIDINE COMPOUNDS
[0057] The present invention provides pyrazolo[3,4-c]pyridine
compounds of Formula I, and pharmaceutical formulations thereof,
which are potentially useful in the treatment of diseases,
conditions and/or disorders modulated by Pim kinases.
[0058] Formula I compounds have the structure:
##STR00003##
[0059] and stereoisomers, geometric isomers, tautomers, or
pharmaceutically acceptable salts thereof, wherein:
[0060] R.sup.1 is selected from --CN, --CH.sub.2CN,
--CH.sub.2CONH.sub.2, --CONH.sub.2, --CONHCH.sub.3,
--CON(CH.sub.3).sub.2, --NHCONH.sub.2, C.sub.3-C.sub.12
carbocyclyl, C.sub.2-C.sub.20 heterocyclyl, C.sub.1-C.sub.20
heteroaryl, --(C.sub.1-C.sub.20 heteroaryl)-(C.sub.1-C.sub.20
heteroaryl), --(C.sub.1-C.sub.20 heteroaryl)-(C.sub.2-C.sub.20
heterocyclyl), --(C.sub.1-C.sub.20 heteroaryl)-O--(C.sub.2-C.sub.20
heterocyclyl), --(C.sub.1-C.sub.20 heteroaryl)-O--(C.sub.1-C.sub.12
alkylene)-(C.sub.2-C.sub.20 heterocyclyl), --(C.sub.1-C.sub.20
heteroaryl)-NR.sup.3--(C.sub.2-C.sub.20 heterocyclyl), and
--(C.sub.1-C.sub.20 heteroaryl)-NR.sup.3--(C.sub.1-C.sub.12
alkylene)-(C.sub.2-C.sub.20 heterocyclyl);
[0061] R.sup.2 is selected from C.sub.1-C.sub.12 alkyl,
C.sub.3-C.sub.12 carbocyclyl, C.sub.2-C.sub.20 heterocyclyl,
C.sub.1-C.sub.20 heteroaryl, C.sub.6-C.sub.20 aryl,
--(C.sub.6-C.sub.20 aryl)-(C.sub.2-C.sub.20 heterocyclyl),
--(C.sub.1-C.sub.12 alkylene)-(C.sub.2-C.sub.20 heterocyclyl),
--(C.sub.1-C.sub.12 alkylene)-NR.sup.3(C.sub.2-C.sub.20
heterocyclyl), --(C.sub.1-C.sub.12
alkylene)-NR.sup.3--(C.sub.1-C.sub.12 alkylene)-(C.sub.2-C.sub.20
heterocyclyl), --(C.sub.1-C.sub.20 heteroaryl)-(C.sub.1-C.sub.20
heteroaryl), --(C.sub.1-C.sub.20 heteroaryl)-(C.sub.2-C.sub.20
heterocyclyl), --(C.sub.1-C.sub.20 heteroaryl)-(C.sub.2-C.sub.20
heterocyclyl)-(C.sub.2-C.sub.20 heterocyclyl), --(C.sub.1-C.sub.20
heteroaryl)-NR.sup.3--(C.sub.2-C.sub.20 heterocyclyl),
--(C.sub.1-C.sub.20 heteroaryl)-(C.sub.1-C.sub.12
alkylene)-(C.sub.2-C.sub.20 heterocyclyl), --(C.sub.1-C.sub.20
heteroaryl)-NR.sup.3--(C.sub.1-C.sub.12 alkylene)-(C.sub.2-C.sub.20
heterocyclyl), and --(C.sub.1-C.sub.20
heteroaryl)-NR.sup.3--(C.sub.1-C.sub.12 alkylene)-(C.sub.1-C.sub.20
heteroaryl);
[0062] R.sup.3 is independently selected from H and
C.sub.1-C.sub.12 alkyl optionally substituted with F, Cl, CN,
--CO.sub.2H, --COCH.sub.3, --CO.sub.2CH.sub.3,
--CO.sub.2C(CH.sub.3).sub.3, --COCH(OH)CH.sub.3, --CONH.sub.2,
--CONHCH.sub.3, --CON(CH.sub.3).sub.2, --NO.sub.2, --NH.sub.2,
--NHCH.sub.3, --N(CH.sub.3).sub.2, --NHCOCH.sub.3,
--N(CH.sub.3)COCH.sub.3, --NHS(O).sub.2CH.sub.3,
--NHCH.sub.2CH.sub.2NH.sub.2, --NHCH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--N(CH.sub.3)C(CH.sub.3).sub.2CONH.sub.2,
--N(CH.sub.3)CH.sub.2CH.sub.2S(O).sub.2CH.sub.3, .dbd.O, --OH,
--OCH.sub.3, --OCH.sub.2CH.sub.2OCH.sub.3,
--OCH.sub.2CH.sub.2NH.sub.2, --S(O).sub.2N(CH.sub.3).sub.2,
--SCH.sub.3, and --S(O).sub.2CH.sub.3;
[0063] where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl,
heterocyclyl, aryl, and heteroaryl are optionally substituted with
one or more groups independently selected from F, Cl, Br, I,
--CH.sub.3, --CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2,
--CH.sub.2CH(CH.sub.3).sub.2, --CH.sub.2NH.sub.2,
--CH.sub.2NHCH.sub.3, --CH.sub.2N(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2CHCH.sub.2NH.sub.2,
--CH.sub.2CHCH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH(CH.sub.3)NH.sub.2, --CH.sub.2CONH.sub.2, --CH.sub.2OH,
--CH.sub.2CH.sub.2OH, --C(CH.sub.3).sub.2OH,
--CH(OH)CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.2CH.sub.2OH,
--CH.sub.2C(CH.sub.3).sub.2OH, --CH.sub.2CH.sub.2SO.sub.2CH.sub.3,
--CN, --CF.sub.3, --CO.sub.2H, --COCH.sub.3, --CO.sub.2CH.sub.3,
--CO.sub.2C(CH.sub.3).sub.3, --COCH(OH)CH.sub.3, --CONH.sub.2,
--CONHCH.sub.3, --CON(CH.sub.3).sub.2,
--C(CH.sub.3).sub.2CONH.sub.2, --NO.sub.2, --NH.sub.2,
--NHCH.sub.3, --N(CH.sub.3).sub.2, --NHCOCH.sub.3,
--N(CH.sub.3)COCH.sub.3, --NHS(O).sub.2CH.sub.3,
--NHCH.sub.2CH.sub.2NH.sub.2, --NHCH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--N(CH.sub.3)C(CH.sub.3).sub.2CONH.sub.2,
--N(CH.sub.3)CH.sub.2CH.sub.2S(O).sub.2CH.sub.3, .dbd.O, --OH,
--OCH.sub.3, --OCH.sub.2CH.sub.2OCH.sub.3,
--OCH.sub.2CH.sub.2NH.sub.2, --S(O).sub.2N(CH.sub.3).sub.2,
--SCH.sub.3, --CH.sub.2OCH.sub.3, --S(O).sub.2CH.sub.3,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl,
piperidinyl, (piperidin-4-yl)ethyl), pyranyl,
(piperidin-4-ylmethyl), morpholinomethyl, and morpholino.
[0064] Exemplary embodiments of Formula I compounds include wherein
R.sup.1 is C.sub.1-C.sub.20 heteroaryl.
[0065] Exemplary embodiments of Formula I compounds include wherein
R.sup.1 is selected from the structures:
##STR00004##
[0066] where the wavy line indicates the site of attachment.
[0067] Exemplary embodiments of Formula I compounds include wherein
R.sup.1 is selected from --CN, --CH.sub.2CN, --CH.sub.2CONH.sub.2,
--CONH.sub.2, --CONHCH.sub.3, --CON(CH.sub.3).sub.2, and
--NHCONH.sub.2. Exemplary embodiments of Formula I compounds
include wherein R.sup.2 is C.sub.1-C.sub.20 heteroaryl.
[0068] Exemplary embodiments of Formula I compounds include wherein
R.sup.2 is --(C.sub.1-C.sub.20 heteroaryl)-(C.sub.2-C.sub.20
heterocyclyl).
[0069] Exemplary embodiments of Formula I compounds include wherein
R.sup.2 is selected from the structures:
##STR00005##
[0070] where the wavy line indicates the site of attachment;
and
[0071] R.sup.4 is selected from F, Cl, Br, I, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2,
--CH.sub.2CH(CH.sub.3).sub.2, --CH.sub.2NH.sub.2,
--CH.sub.2NHCH.sub.3, --CH.sub.2N(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2CHCH.sub.2NH.sub.2,
--CH.sub.2CHCH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH(CH.sub.3)NH.sub.2, --CH.sub.2CONH.sub.2, --CH.sub.2OH,
--CH.sub.2CH.sub.2OH, --C(CH.sub.3).sub.2OH,
--CH(OH)CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.2CH.sub.2OH,
--CH.sub.2C(CH.sub.3).sub.2OH, --CH.sub.2CH.sub.2SO.sub.2CH.sub.3,
--CN, --CF.sub.3, --CO.sub.2H, --COCH.sub.3, --CO.sub.2CH.sub.3,
--CO.sub.2C(CH.sub.3).sub.3, --COCH(OH)CH.sub.3, --CONH.sub.2,
--CONHCH.sub.3, --CON(CH.sub.3).sub.2,
--C(CH.sub.3).sub.2CONH.sub.2, --NO.sub.2, --NH.sub.2,
--NHCH.sub.3, --N(CH.sub.3).sub.2, --NHCOCH.sub.3,
--N(CH.sub.3)COCH.sub.3, --NHS(O).sub.2CH.sub.3,
--NHCH.sub.2CH.sub.2NH.sub.2, --NHCH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--N(CH.sub.3)C(CH.sub.3).sub.2CONH.sub.2,
--N(CH.sub.3)CH.sub.2CH.sub.2S(O).sub.2CH.sub.3, .dbd.O, --OH,
--OCH.sub.3, --OCH.sub.2CH.sub.2OCH.sub.3,
--OCH.sub.2CH.sub.2NH.sub.2, --S(O).sub.2N(CH.sub.3).sub.2,
--SCH.sub.3, --CH.sub.2OCH.sub.3, --S(O).sub.2CH.sub.3,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl,
piperidinyl, (piperidin-4-yl)ethyl), pyranyl,
(piperidin-4-ylmethyl), morpholinomethyl, and morpholino; and
[0072] n is 0, 1, or 2.
[0073] Exemplary embodiments of Formula I compounds include
compounds having the structure of Formula Ia:
##STR00006##
[0074] where R.sup.4 is selected from F, Cl, Br, I, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2,
--CH.sub.2CH(CH.sub.3).sub.2, --CH.sub.2NH.sub.2,
--CH.sub.2NHCH.sub.3, --CH.sub.2N(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2CHCH.sub.2NH.sub.2,
--CH.sub.2CHCH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH(CH.sub.3)NH.sub.2, --CH.sub.2CONH.sub.2, --CH.sub.2OH,
--CH.sub.2CH.sub.2OH, --C(CH.sub.3).sub.2OH,
--CH(OH)CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.2CH.sub.2OH,
--CH.sub.2C(CH.sub.3).sub.2OH, --CH.sub.2CH.sub.2SO.sub.2CH.sub.3,
--CN, --CF.sub.3, --CO.sub.2H, --COCH.sub.3, --CO.sub.2CH.sub.3,
--CO.sub.2C(CH.sub.3).sub.3, --COCH(OH)CH.sub.3, --CONH.sub.2,
--CONHCH.sub.3, --CON(CH.sub.3).sub.2,
--C(CH.sub.3).sub.2CONH.sub.2, --NO.sub.2, --NH.sub.2,
--NHCH.sub.3, --N(CH.sub.3).sub.2, --NHCOCH.sub.3,
--N(CH.sub.3)COCH.sub.3, --NHS(O).sub.2CH.sub.3,
--NHCH.sub.2CH.sub.2NH.sub.2, --NHCH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--N(CH.sub.3)C(CH.sub.3).sub.2CONH.sub.2,
--N(CH.sub.3)CH.sub.2CH.sub.2S(O).sub.2CH.sub.3, .dbd.O, --OH,
--OCH.sub.3, --OCH.sub.2CH.sub.2OCH.sub.3,
--OCH.sub.2CH.sub.2NH.sub.2, --S(O).sub.2N(CH.sub.3).sub.2,
--SCH.sub.3, --CH.sub.2OCH.sub.3, --S(O).sub.2CH.sub.3,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl,
piperidinyl, (piperidin-4-yl)ethyl), pyranyl,
(piperidin-4-ylmethyl), morpholinomethyl, and morpholino; and
[0075] n is 0, 1, or 2.
[0076] Exemplary embodiments of Formula I compounds include
compounds having the structure of Formula Ib:
##STR00007##
[0077] where R.sup.3 is selected from H, C.sub.3-C.sub.12
carbocyclyl, and C.sub.1-C.sub.12 alkyl where carbocyclyl and alkyl
are optionally substituted with F, Cl, CN, --CO.sub.2H,
--COCH.sub.3, --CO.sub.2CH.sub.3, --CO.sub.2C(CH.sub.3).sub.3,
--COCH(OH)CH.sub.3, --CONH.sub.2, --CONHCH.sub.3,
--CON(CH.sub.3).sub.2, --NO.sub.2, --NH.sub.2, --NHCH.sub.3,
--N(CH.sub.3).sub.2, --NHCOCH.sub.3, --N(CH.sub.3)COCH.sub.3,
--NHS(O).sub.2CH.sub.3, --NHCH.sub.2CH.sub.2NH.sub.2,
--NHCH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--N(CH.sub.3)C(CH.sub.3).sub.2CONH.sub.2,
--N(CH.sub.3)CH.sub.2CH.sub.2S(O).sub.2CH.sub.3, .dbd.O, --OH,
--OCH.sub.3, --OCH.sub.2CH.sub.2OCH.sub.3,
--OCH.sub.2CH.sub.2NH.sub.2, --S(O).sub.2N(CH.sub.3).sub.2,
--SCH.sub.3, and --S(O).sub.2CH.sub.3; and
[0078] n is 0, 1, or 2.
[0079] Exemplary embodiments of Formula I compounds include
compounds having the structure of Formula Ic:
##STR00008##
[0080] where R.sup.4 is selected from F, Cl, Br, I, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH(CH.sub.3).sub.2,
--CH.sub.2CH(CH.sub.3).sub.2, --CH.sub.2NH.sub.2,
--CH.sub.2NHCH.sub.3, --CH.sub.2N(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2NH.sub.2, --CH.sub.2CHCH.sub.2NH.sub.2,
--CH.sub.2CHCH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH(CH.sub.3)NH.sub.2, --CH.sub.2CONH.sub.2, --CH.sub.2OH,
--CH.sub.2CH.sub.2OH, --C(CH.sub.3).sub.2OH,
--CH(OH)CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.2CH.sub.2OH,
--CH.sub.2C(CH.sub.3).sub.2OH, --CH.sub.2CH.sub.2SO.sub.2CH.sub.3,
--CN, --CF.sub.3, --CO.sub.2H, --COCH.sub.3, --CO.sub.2CH.sub.3,
--CO.sub.2C(CH.sub.3).sub.3, --COCH(OH)CH.sub.3, --CONH.sub.2,
--CONHCH.sub.3, --CON(CH.sub.3).sub.2,
--C(CH.sub.3).sub.2CONH.sub.2, --NO.sub.2, --NH.sub.2,
--NHCH.sub.3, --N(CH.sub.3).sub.2, --NHCOCH.sub.3,
--N(CH.sub.3)COCH.sub.3, --NHS(O).sub.2CH.sub.3,
--NHCH.sub.2CH.sub.2NH.sub.2, --NHCH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--N(CH.sub.3)C(CH.sub.3).sub.2CONH.sub.2,
--N(CH.sub.3)CH.sub.2CH.sub.2S(O).sub.2CH.sub.3, .dbd.O, --OH,
--OCH.sub.3, --OCH.sub.2CH.sub.2OCH.sub.3,
--OCH.sub.2CH.sub.2NH.sub.2, --S(O).sub.2N(CH.sub.3).sub.2,
--SCH.sub.3, --CH.sub.2OCH.sub.3, --S(O).sub.2CH.sub.3,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl,
piperidinyl, (piperidin-4-yl)ethyl), pyranyl,
(piperidin-4-ylmethyl), morpholinomethyl, and morpholino; and
[0081] n is 0, 1, or 2.
Biological Evaluation
[0082] Determination of the Pim kinase activity of a Formula I
compound is possible by a number of direct and indirect detection
methods. Certain exemplary compounds described herein were assayed
for their Pim kinase binding activity, including isoforms Pim-1,
Pim-2, and Pim-3, (Example 901) and in vitro activity against tumor
cells (Example 902). Certain exemplary compounds of the invention
had Pim binding activity IC.sub.50 values less than about 1
micromolar (.mu.M). Certain compounds of the invention had tumor
cell-based activity EC.sub.50 values less than about 1 micromolar
(.mu.M).
[0083] Exemplary Formula I compounds in Table 1 were made,
characterized, and tested for inhibition of Pim kinase according to
the methods of this invention, and have the following structures
and corresponding names (ChemBioDraw Ultra, Version 11.0,
CambridgeSoft Corp., Cambridge Mass.).
TABLE-US-00001 TABLE 1 Pim-1 No. Structure Name Ki (.mu.m) 101
##STR00009## 3-methyl-5-(pyridin-3-yl)- 1H-pyrazolo[3,4-c]pyridine
0.19 102 ##STR00010## 3-mcthyl-5-(1H-pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridine 0.302 103 ##STR00011##
3-methyl-5-(1H-pyrazol-5-yl)-1H- pyrazolo[3,4-c]pyridine 1.3 104
##STR00012## (S)-1-((5-(pyridin-3-yl)- 1H-pyrazolo[3,4-c]pyridin-
3-yl)methyl)piperidin-3-amine 3.0 105 ##STR00013##
(R)-1-((5-(pyridin-3-yl)- 1H-pyrazolo[3,4-c]pyridin-
3-yl)methyl)piperidin-3-amine 3.4 106 ##STR00014##
1-((5-(pyridin-3-yl)-1H- pyrazolo[3,4-c]pyridin-3-
yl)methyl)piperidin-4-amine 1.4 107 ##STR00015##
(S)-1-((5-(1H-pyrazol-4-yl)- 1H-pyrazolo[3,4-c]pyridin-
3-yl)methyl)piperidin-3-amine 3.0 108 ##STR00016##
1-((5-(1H-pyrazol-4-yl)- 1H-pyrazolo[3,4-c]pyridin-
3-yl)methyl)piperidin-4-amine 1.1 109 ##STR00017##
N-((5-(pyridin-3-yl)-1H- pyrazolo[3,4-c]pyridin-3-
yl)methyl)piperidin-4-amine 3.8 110 ##STR00018## 1-(6-(3-methyl-1H-
pyrazolo[3,4-c]pyridin-5- yl)pyrazin-2-yl)piperidin-4-amine 0.0058
111 ##STR00019## (S)-1-((5-(1H-pyrazol-4-yl)-
1H-pyrazolo[3,4-c]pyridin-3- yl)methyl)piperidin-3-amine 4.0 112
##STR00020## (S)-1-(3-(3-methyl-1H- pyrazolo[3,4-c]pyridin-5-
yl)pyridin-4-yl)piperidin-3-amine 3.5 113 ##STR00021##
1-(piperidin-4-yl)-N-((5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)methyl)methanamine 3.2 114
##STR00022## 3-methyl-5-(1-(oxetan-3-yl)-1H- pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridine 0.844 115 ##STR00023##
3-methyl-5-(pyrimidin-5-yl)- 1H-pyrazolo[3,4-c]pyridine 3.5 116
##STR00024## 3-phenyl-5-(pyridin-3-yl)- 1H-pyrazolo[3,4-c]pyridine
0.00965 117 ##STR00025## 3-(2-fluorophenyl)-5-(pyridin-
3-yl)-1H-pyrazolo[3,4-c]pyridinc 0.0122 118 ##STR00026##
3-methyl-5-(pyrazin-2-yl)- 1H-pyrazolo[3,4-c]pyridine 0.62 119
##STR00027## (R)-1-(3-(3-methyl-1H- pyrazolo[3,4-c]pyridin-5-
yl)pyridin-4-yl)piperidin-3-amine 1.1 120 ##STR00028##
(S)-1-(6-(3-methyl-1H- pyrazolo[3,4-c]pyridin-5-
yl)pyrazin-2-yl)piperidin-3-amine 0.00478 121 ##STR00029##
(R)-1-(6-(3-methyl-1H- pyrazolo[3,4-c]pyridin-5-
yl)pyrazin-2-yl)piperidin-3-amine 0.00691 122 ##STR00030##
5-(3-fluorophenyl)-3-methyl- 1H-pyrazolo[3,4-c]pyridine 2.2 123
##STR00031## 5-(5-fluoropyridin-3-yl)-3-methyl-
1H-pyrazolo[3,4-c]pyridine 0.737 124 ##STR00032##
(S)-1-(3-(3-(2-fluorophenyl)-1H-
pyrazolo[3,4-c]pyridin-5-yl)pyridin- 4-yl)piperidin-3-amine 0.0142
125 ##STR00033## 3-(5-(pyridin-3-yl)-1H- pyrazolo[3,4-c]pyridin-3-
yl)benzamide 0.307 126 ##STR00034## 5-(pyridin-3-yl)-3-(3-
(trifluoromethyl)phenyl)- 1H-pyrazolo[3,4-c]pyridine 0.0159 127
##STR00035## 3-methyl-5-(1-methyl-1H-pyrazol-
4-yl)-1H-pyrazolo[3,4-c]pyridine 0.261 128 ##STR00036##
1-(3-(3-(2-fluorophenyl)-1H- pyrazolo[3,4-c]pyridin-5-
yl)pyridin-4-yl)piperidin-4-amine 1.5 129 ##STR00037##
3-(2-fluorophenyl)-5-(1-methyl-1H- pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridine 0.00785 130 ##STR00038##
(S)-(1-(3-(3-(2-fluorophenyl)- 1H-pyrazolo[3,4-c]pyridin-5-
yl)pyridin-4-yl)pyrrolidin-3- yl)methanamine 1.5 131 ##STR00039##
3-(6-fluoropyridin-2-yl)-5-(pyridin-
3-yl)-1H-pyrazolo[3,4-c]pyridine 0.0131 132 ##STR00040##
6-(5-(pyridin-3-yl)-1H- pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2(1H)-one 0.13 133 ##STR00041##
5-(1-methyl-1H-pyrazol-4-yl)-3- phenyl-1H-pyrazolo[3,4-c]pyridine
0.00557 134 ##STR00042## 2-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)acetonitrile 0.826 135 ##STR00043##
2-(5-(1-methyl-1H-pyrazol-4-yl)-1H- pyrazolo[3,4-c]pyridin-3-
yl)acetonitrile 0.387 136 ##STR00044##
3-(2-fluorophenyl)-5-(1H-pyrazol-4- yl)-1H-pyrazolo[3,4-c]pyridine
0.00869 137 ##STR00045## 3-phenyl-5-(1H-pyrazol-4-yl)-
1H-pyrazolo[3,4-c]pyridine 0.00461 138 ##STR00046##
3-(2-fluorophenyl)-5-(pyrimidin-5- yl)-1H-pyrazolo[3,4-c]pyridine
0.577 139 ##STR00047## 1-(3-(3-(2-fluorophenyl)-
1H-pyrazolo[3,4-c]pyridin-5- yl)pyridin-4-yl)azepan-4-amine 0.255
140 ##STR00048## (S)-(1-(3-(3-(2-fluorophenyl)-1H-
pyrazolo[3,4-c]pyridin-5-yl)pyridin-
4-yl)piperidin-3-yl)methanamine 0.412 141 ##STR00049##
(R)-1-(3-(3-(2-fluorophenyl)- 1H-pyrazolo[3,4-c]pyridin-5-
yl)pyridin-4-yl)piperidin-3-amine 0.142 142 ##STR00050##
3-phenyl-5-(1H-1,2,4-triazol-1- yl)-1H-pyrazolo[3,4-c]pyridine
0.306 143 ##STR00051## N1-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)ethane-1,2-diamine
0.000312 144 ##STR00052## 1-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-4-amine
0.0000839 145 ##STR00053## 2-(5-(1H-pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)acetonitrile 0.324 146 ##STR00054##
5-(1H-imidazol-1-yl)-3-phenyl- 1H-pyrazolo[3,4-c]pyridine 0.0267
147 ##STR00055## 1-(6-(3-(2-fluorophenyl)-1H-
pyrazolo[3,4-c]pyridin-5- yl)pyrazin-2-yl)piperidin-4-amine
0.000121 148 ##STR00056## (S)-3-(2-fluorophenyl)-5-(4-
(piperidin-3-yloxy)pyridin-3-yl)- 1H-pyrazolo[3,4-c]pyridine
0.000342 149 ##STR00057## (R)-1-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-amine
0.000027 150 ##STR00058## 3-phenyl-5-(pyrimidin-5-yl)-
1H-pyrazolo[3,4-c]pyridine 0.209 151 ##STR00059##
(S)-1-(6-(3-(2-fluorophenyl)- 1H-pyrazolo[3,4-c]pyridin-5-
yl)pyrazin-2-yl)pyrrolidin-3-amine 0.000179 152 ##STR00060##
(S)-1-(6-(3-(2-fluorophenyl)-1H- pyrazolo[3,4-c]pyridin-5-
yl)pyrazin-2-yl)piperidin-3-amine 0.00012 153 ##STR00061##
(R)-1-(6-(3-(2-fluorophenyl)-1H- pyrazolo[3,4-c]pyridin-5-
yl)pyrazin-2-yl)piperidin-3-amine 0.000114 154 ##STR00062##
(R)-1-(6-(3-(2-fluorophenyl)-1H- pyrazolo[3,4-c]pyridin-5-
yl)pyrazin-2-yl)pyrrolidin-3-amine 0.000302 155 ##STR00063##
3-(2-fluorophenyl)-5-(4- (piperidin-4-ylmethoxy)pyridin-
3-yl)-1H-pyrazolo[3,4-c]pyridine 0.000614 156 ##STR00064##
3-(1H-pyrazol-4-yl)-5-(pyridin- 3-yl)-1H-pyrazolo[3,4-c]pyridine
0.00231 157 ##STR00065## 1-(5-(3-(2-fluorophenyl)-1H-
pyrazolo[3,4-c]pyridin-5- yl)pyridin-3-yl)piperidin-4-amine 0.00131
158 ##STR00066## 1-(5-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-3-yl)piperidin-4-amine 0.0021
159 ##STR00067## N1-(4-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)ethane-1,2-diamine
0.000941 160 ##STR00068## 1-(4-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-4-amine 0.00278
161 ##STR00069## (S)-1-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-amine
0.0000411 162 ##STR00070## 3-(6-(piperazin-1-yl)pyridin-2-yl)-5-
(pyridin-3-yl)-1H- pyrazolo[3,4-c]pyridine 0.000037 163
##STR00071## 3,5-bis(1-methyl-1H-pyrazol-4-
yl)-1H-pyrazolo[3,4-c]pyridine 0.00192 164 ##STR00072##
(R)-(1-(5-(3-(2-fluorophenyl)-1H-
pyrazolo[3,4-c]pyridin-5-yl)pyridin-
3-yl)pyrrolidin-3-yl)methanamine 0.0019 165 ##STR00073##
(1-(5-(5-(pyridin-3-yl)-1H- pyrazolo[3,4-c]pyridin-3-yl)pyridin-
3-yl)piperidin-4-yl)methanamine 0.000985 166 ##STR00074##
1-(5-(3-(2-fluorophenyl)-1H- pyrazolo[3,4-c]pyridin-5-
yl)pyridin-3-yl)azepan-4-amine 0.000574 167 ##STR00075##
(1-(5-(3-(2-fluorophenyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)pyridin-
3-yl)piperidin-4-yl)methanamine 0.00171 168 ##STR00076##
(R)-(1-(5-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin-
3-yl)pyrrolidin-3-yl)methanamine 0.0016 169 ##STR00077##
1-(5-(5-(pyridin-3-yl)-1H- pyrazolo[3,4-c]pyridin-3-
yl)pyridin-3-yl)azepan-4-amine 0.00135 170 ##STR00078##
N-(piperidin-4-yl)-5-(5-(pyridin- 3-yl)-1H-pyrazolo[3,4-c]pyridin-
3-yl)pyridin-3-amine 0.000443 171 ##STR00079##
5-(3-(2-fluorophenyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)-N-
(piperidin-4-yl)pyridin-3-amine 0.00242 172 ##STR00080##
3-(2-fluoro-5-methoxyphenyl)-5- (1-methyl-1H-pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridine 0.00376 173 ##STR00081##
(S)-1-(6-(5-(1-methyl-1H- pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-amine
0.000060 174 ##STR00082## 1-(6-(5-(1-methyl-1H-pyrazol-
4-yl)-1H-pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)piperidin-4-amine 0.000086 175 ##STR00083##
3-(1-(piperidin-4-yl)-1H-pyrazol- 4-yl)-5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridine 0.00030 176 ##STR00084##
3,5-di(pyridin-3-yl)-1H- pyrazolo[3,4-c]pyridine 0.00646 177
##STR00085## (R)-1-(6-(5-(1-methyl-1H- pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-amine
0.0000355 178 ##STR00086## 2-(4-(3-(6-fluoropyridin-2-yl)-
1H-pyrazolo[3,4-c]pyridin- 5-yl)-1H-pyrazol-1-yl)acetamide 0.0176
179 ##STR00087## (S)-1-(6-(3-(2-fluorophenyl)-1H-
pyrazolo[3,4-c]pyridin-5- yl)pyrazin-2-yl)azepan-4-amine
0.000061
180 ##STR00088## (S)-1-(5-(3-(2-fluorophcnyl)-1H-
pyrazolo[3,4-c]pyridin-5- yl)pyridin-3-yl)piperidin-3-amine
0.000264 181 ##STR00089## 3-(6-(piperazin-1-yl)pyridin-2-yl)-5-
(tetrahydro-2H-pyran-3-yl)-1H- pyrazolo[3,4-c]pyridine 0.00396 182
##STR00090## (1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-
1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-4-
yl)methanamine 0.000085 183 ##STR00091##
6-(5-(1-methyl-1H-pyrazol-4-yl)-1H- pyrazolo[3,4-c]pyridin-3-yl)-N-
(pipcridin-4-ylmethyl)pyridin-2-amine 0.000426 184 ##STR00092##
5-(1-methyl-1H-pyrazol-4-yl)-3-(6-
(1-methyl-1H-pyrazol-4-yl)pyridin- 2-yl)-1H-pyrazolo[3,4-c]pyridine
0.000502 185 ##STR00093## 5-(furan-3-yl)-3-phenyl-1H-
pyrazolo[3,4-c]pyridine 0.0709 186 ##STR00094##
3-(1-(piperidin-4-ylmethyl)-1H- pyrazol-4-yl)-5-(pyridin-3-yl)-
1H-pyrazolo[3,4-c]pyridine 0.000717 187 ##STR00095##
3-(6-(1,4-diazepan-1-yl)pyridin- 2-yl)-5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridine 0.000015 188 ##STR00096##
1-(6-(5-(1-methyl-1H-pyrazol-4- yl)-1H-pyrazolo[3,4-c]pyridin-
3-yl)pyridin-2-yl)azepan-4-amine 0.000039 189 ##STR00097##
(R)-1-(6-(5-(1-methyl-1H-pyrazol- 4-yl)-1H-pyrazolo[3,4-c]pyridin-
3-yl)pyridin-2-yl)pyrrolidin-3-amine 0.000136 190 ##STR00098##
(S)-1-(5-(3-(2-fluorophenyl)-1H-
pyrazolo[3,4-c]pyridin-5-yl)pyridin- 3-yl)pyrrolidin-3-aminc
0.00027 191 ##STR00099## (R)-1-(5-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-amine
0.000404 192 ##STR00100## (R)-1-(5-(3-(2-fluorophenyl)-
1H-pyrazolo[3,4-c]pyridin-5- yl)pyridin-3-yl)pyrrolidin-3-aminc
0.000511 193 ##STR00101## 3-(1H-pyrazol-3-yl)-5-(pyridin-
3-yl)-1H-pyrazolo[3,4-c]pyridine 0.00263 194 ##STR00102##
5-(pyridin-3-yl)-3-(pyridin-4-yl)- 1H-pyrazolo[3,4-c]pyridine
0.00877 195 ##STR00103## 3-(2-fluorophenyl)-5-(4-
(piperidin-4-yloxy)pyridin-3-yl)- 1H-pyrazolo[3,4-c]pyridine
0.000567 196 ##STR00104## (S)-1-(5-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-amine
0.000774 197 ##STR00105## 1-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)azepan-4-amine 0.000038
198 ##STR00106## 5-(4-(azetidin-3-yloxy)pyridin-
3-yl)-3-(2-fluorophenyl)-1H- pyrazolo[3,4-c]pyridine 0.00312 199
##STR00107## (R)-3-(2-fluorophenyl)-5-(4-
(piperidin-3-ylmethoxy)pyridin- 3-yl)-1H-pyrazolo[3,4-c]pyridine
0.000354 200 ##STR00108## 6-(5-(1-methyl-1H-pyrazol-4-yl)-
1H-pyrazolo[3,4-c]pyridin-3-yl)- N-(piperidin-4-yl)pyridin-2-amine
0.000092 201 ##STR00109## (S)-3-(2-fluorophenyl)-5-(4-
(piperidin-3-ylmethoxy)pyridin- 3-yl)-1H-pyrazolo[3,4-c]pyridine
0.00152 202 ##STR00110## (S)-1-(5-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)pyrrolidin-3-amine 0.0010
203 ##STR00111## (R)-1-(5-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)pyrrolidin-3-amine
0.00102 204 ##STR00112## 3-(pyridin-2-yl)-5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridine 0.0116 205 ##STR00113##
3-(2-fluoro-5-methylphenyl)-5- (1-methyl-1H-pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridine 0.00608 206 ##STR00114##
(S)-1-(6-(5-(5-fluoropyridin-3- yl)-1H-pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)piperidin-3-aminc 0.000172 207 ##STR00115##
3-(3-(2-fluorophenyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)-N-
(piperidin-4-ylmethyl)pyridin-4-amine 0.0227 208 ##STR00116##
5-(5-fluoropyridin-3-yl)-3-(6- (piperazin-1-yl)pyridin-2-yl)-
1H-pyrazolo[3,4-c]pyridine 0.000284 209 ##STR00117##
(R)-3-(2-fluorophenyl)-5-(4- (pyrrolidin-3-ylmethoxy)pyridin-
3-yl)-1H-pyrazolo[3,4-c]pyridine 0.000189 210 ##STR00118##
(R)-1-(6-(5-(5-fluoropyridin-3- yl)-1H-pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)piperidin-3-amine 0.000206 211 ##STR00119##
(S)-3-(2-fluorophcnyl)-5-(4- (pyrrolidin-3-ylmethoxy)pyridin-
3-yl)-1H-pyrazolo[3,4-c]pyridine 0.00128 212 ##STR00120##
3-(6-(piperazin-1-yl)pyridin-2- yl)-5-(tetrahydrofuran-3-yl)-1H-
pyrazolo[3,4-c]pyridine 0.00848 213 ##STR00121##
5-(1H-imidazol-5-yl)-3-phenyl- 1H-pyrazolo[3,4-c]pyridine 214
##STR00122## 3-phenyl-5-(pyrazin-2-yl)-1H- pyrazolo[3,4-c]pyridine
0.0416 215 ##STR00123## 3-(1-(piperidin-4-yl)-1H-
pyrazol-3-yl)-5-(pyridin-3- yl)-1H-pyrazolo[3,4-c]pyridine 0.000313
216 ##STR00124## 3-(6-((1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-
yl)pyridin-2-yl)-5-(1-methyl-1H- pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridine 0.000126 217 ##STR00125##
N-(2-(1H-imidazol-4-yl)ethyl)-6-(5- (1-methyl-1H-pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin- 2-amine -.000297 218
##STR00126## 3-(2-fluorophenyl)-5-(1H-imidazol-
5-yl)-1H-pyrazolo[3,4-c]pyridine 0.0309 219 ##STR00127##
3-(2-fluorophenyl)-5-(pyrazin- 2-yl)-1H-pyrazolo[3,4-c]pyridine
0.0335 220 ##STR00128## 3-(2-fluorophenyl)-5-(4-(2-
(piperidin-4-yl)ethoxy)pyridin-3- yl)-1H-pyrazolo[3,4-c]pyridine
0.000379 221 ##STR00129## 1-(6-(3-(1-methyl-1H-pyrazol-4-yl)-
1H-pyrazolo[3,4-c]pyridin-5- yl)pyrazin-2-yl)piperidin-4-amine
0.000096 222 ##STR00130## (R)-1-(3-(5-(1-methyl-1H-pyrazol-
4-yl)-1H-pyrazolo[3,4-c]pyridin- 3-yl)phenyl)piperidin-3-amine
0.000387 223 ##STR00131## 1-methyl-4-(3-(6-(piperazin-1-
yl)pyridin-2-yl)-1H- pyrazolo[3,4-c]pyridin-5- yl)piperazin-2-one
0.0385 224 ##STR00132## 1-(3-(6-(piperazin-1-yl)pyridin-2-yl)-
1H-pyrazolo[3,4-c]pyridin-5-yl)urea 0.00196 225 ##STR00133##
3-cyclopentenyl-5-(pyridin-3-yl)- 1H-pyrazolo[3,4-c]pyridine
0.00283 226 ##STR00134## 1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-
1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)azcpan-3-amine
0.000051 227 ##STR00135## (S)-1-(6-(5-(1-methyl-1H-pyrazol-
4-yl)-1H-pyrazolo[3,4-c]pyridin- 3-yl)pyridin-2-yl)azepan-4-amine
0.000069 228 ##STR00136## 3-cyclopentyl-5-(pyridin-3-yl)-
1H-pyrazolo[3,4-c]pyridine 0.043 229 ##STR00137##
4-amino-1-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin- 2-yl)piperidine-4-carboxamide
0.00022 230 ##STR00138## 1-(6-(3-(2,6-difluorophenyl)-
1H-pyrazolo[3,4-c]pyridin-5- yl)pyrazin-2-yl)piperidin-4-amine 231
##STR00139## 1-(6-(3-phenyl-1H- pyrazolo[3,4-c]pyridin-5-
yl)pyrazin-2-yl)piperidin-4-amine 232 ##STR00140##
3-(1-methyl-1H-pyrazol-3-yl)-5- (pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridine 0.00716 233 ##STR00141##
1-(6-(3-(1-methyl-1H-pyrazol-3- yl)-1H-pyrazolo[3,4-c]pyridin-5-
yl)pyrazin-2-yl)piperidin-4-aminc 0.000051 234 ##STR00142##
5-(1-methyl-1H-pyrazol-4-yl)-3- (6-(piperazin-1-yl)pyridin-2-yl)-
1H-pyrazolo[3,4-c]pyridine 0.000036 235 ##STR00143##
2-(3-(6-(piperazin-1-yl)pyridin- 2-yl)-1H-pyrazolo[3,4-c]pyridin-
5-yl)acetonitrile 0.583 236 ##STR00144##
4-amino-N-methyl-1-(6-(5-(pyridin- 3-yl)-1H-pyrazolo[3,4-c]pyridin-
3-yl)pyridin-2-yl)piperidine-4- carboxamide 0.000353 237
##STR00145## (R)-2-(1-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin- 2-yl)piperidin-3-yl)ethanamine
0.000042 238 ##STR00146## 3-(3-(6-(piperazin-1-yl)pyridin-2-
yl)-1H-pyrazolo[3,4-c]pyridin-5- yl)pyridin-2-amine 0.000267 239
##STR00147## (1S,3R)-N1-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin- 2-yl)cyclohexane-1,3-diamine
0.00030 240 ##STR00148## 3-(piperazin-1-yl)-5-(5-(pyridin-3-yl)-
1H-pyrazolo[3,4-c]pyridin-3- yl)benzonitrile 0.00528 241
##STR00149## 1-(3-chloro-6-(5-(pyridin-3-yl)-
1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-4-amine
0.000096 242 ##STR00150## (S)-2-(1-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin- 2-yl)piperidin-3-yl)ethanamine
0.000030 243 ##STR00151## 1-(3-methyl-6-(5-(pyridin-3-yl)-
1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-4-amine
0.000049 244 ##STR00152## (R)-1-(6-(3-(2-fluorophenyl)-
1H-pyrazolo[3,4-c]pyridin-5- yl)pyrazin-2-yl)azepan-4-amine
0.000030 245 ##STR00153## (1R,3S)-N1-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin- 2-yl)cyclohexane-1,3-diamine
0.0000079 246 ##STR00154## (R)-1-(6-(5-(1-methyl-1H-pyrazol-4-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)azepan-4-amine
0.000030 247 ##STR00155## 5-(1-methyl-1H-pyrazol-4-yl)-3-(6-
(piperidin-4-yl)pyridin-2-yl)-1H- pyrazolo[3,4-c]pyridine 0.000224
248 ##STR00156## (S)-1-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)azepan-4-amine 0.000048
249 ##STR00157## (R)-1-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)azepan-4-amine 0.000020
250 ##STR00158## 2-methyl-1-(4-(5-(1-methyl-1H- pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)-1H- pyrazol-1-yl)propan-2-ol 0.000389
251 ##STR00159## 1s,4s)-N1-(6-(5-(1-methyl-1H-pyrazol-
4-yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)cyclohexane-1,4-
diamine 0.000040 252 ##STR00160##
5-(pyridin-3-yl)-3-(pyrrolidin-1-yl)- 1H-pyrazolo[3,4-c]pyridine
0.010 253 ##STR00161## 2-(3-(6-(piperazin-1-yl)pyridin-2-yl)-
1H-pyrazolo[3,4-c]pyridin-5- yl)acetamide 0.171 254 ##STR00162##
1-methyl-3-(5-(pyridin-3-yl)-1H- pyrazolo[3,4-c]pyridin-3-
yl)imidazolidin-2-one 0.0185 255 ##STR00163##
3-(5-chloro-6-(4-methylpiperazin-
1-yl)pyridin-2-yl)-5-(pyridin-3-yl)- 1H-pyrazolo[3,4-c]pyridine
0.000113
256 ##STR00164## 3,5-di(pyridin-2-yl)-1H- pyrazolo[3,4-c]pyridine
1.5 257 ##STR00165## 3-(5-methyl-6-(4-methylpiperazin-1-
yl)pyridin-2-yl)-5-(pyridin-3-yl)- 1H-pyrazolo[3,4-c]pyridine
0.000032 258 ##STR00166## 1-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyrrolidin-2-one 0.0809 259
##STR00167## 1-methyl-4-(3-phenyl-1H- pyrazolo[3,4-c]pyridin-5-yl)-
1H-pyrrol-2(5H)-one 0.92 260 ##STR00168## 1-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)piperidin-2-one 1.1 261 ##STR00169##
3-(6-(piperidin-1-yl)pyridin-2-yl)- 5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridine 0.000415 262 ##STR00170##
1-(6-(5-(1-methyl-1H-pyrazol-4- yl)-1H-pyrazolo[3,4-c]pyridin-
3-yl)pyridin-2-yl)piperidin-3-ol 0.000071 263 ##STR00171##
1-methyl-4-(3-phenyl-1H- pyrazolo[3,4-c]pyridin-5-yl)pyrrolidin-
2-one 0.241 264 ##STR00172## (R)-5-(1-methyl-1H-pyrazol-4-yl)-3-
(6-(piperidin-3-yloxy)pyridin-2-yl)- 1H-pyrazolo[3,4-c]pyridine
0.00027 265 ##STR00173## (S)-1-(3-chloro-6-(5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-amine
0.000019 266 ##STR00174## (R)-1-(3-chloro-6-(5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-amine
0.000060 267 ##STR00175## 4-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)morpholine 0.000262 268
##STR00176## (S)-1-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin- 2-yl)pyrrolidin-3-amine
0.0000268 269 ##STR00177## (S)-(1-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin-
2-yl)pyrrolidin-3-yl)methanamine 0.000113 270 ##STR00178##
(R)-(1-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin-
2-yl)pyrrolidin-3-yl)methanamine 0.000085 271 ##STR00179##
(R)-1-(6-(5-(pyridin-3-yl)-1H- pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)piperidin-3-ol 0.000073 272 ##STR00180##
1-(6-(5-(pyridin-3-yl)-1H- pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)piperidin-4-ol 0.000149 273 ##STR00181##
3-(6-(4,4'-bipiperidin-1-yl)pyridin- 2-yl)-5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridine 0.00007 274 ##STR00182##
3-(6-fluoro-5-methylpyridin-2-yl)-5- (pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridine 0.00477 275 ##STR00183##
3-(5-methylpyridin-2-yl)-5-(pyridin-
3-yl)-1H-pyrazolo[3,4-c]pyridine 0.00692 276 ##STR00184##
(R)-1-(6-(5-(pyridin-3-yl)-1H- pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)pyrrolidin-3-amine 0.000188 277 ##STR00185##
(S)-1-(6-(5-(pyridin-3-yl)-1H- pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)piperidin-3-ol 278 ##STR00186##
(1-(6-(5-(pyridin-3-yl)-1H- pyrazolo[3,4-c]pyridin-3-yl)pyridin-
2-yl)piperidin-4-yl)methanamine 0.00010 279 ##STR00187##
4-(6-(5-(pyridin-3-yl)-1H- pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)piperazin-2-one 0.000351 280 ##STR00188##
N1-(6-(5-(pyridin-3-yl)-1H- pyrazolo[3,4-c]pyridin-3-yl)pyridin-
2-yl)propane-1,3-diamine 281 ##STR00189##
3-(3,4-dihydro-2H-pyran-5-yl)-5- (pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridine 0.0288 282 ##STR00190##
2-(4-(6-(5-(pyridin-3-yl)-1H- pyrazolo[3,4-c]pyridin-3-yl)pyridin-
2-yl)piperazin-1-yl)ethanol 0.000164 283 ##STR00191##
N1-(6-(5-(pyridin-3-yl)-1H- pyrazolo[3,4-c]pyridin-3-yl)pyridin-
2-yl)butane-1,4-diamine 0.000257 284 ##STR00192##
3-(4,5-dihydrofuran-3-yl)-5-(pyridin-
3-yl)-1H-pyrazolo[3,4-c]pyridinc 0.0106 285 ##STR00193##
(R)-1-(6-(5-(1-ethyl-1H-pyrazol- 4-yl)-1H-pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)piperidin-3-aminc 0.0000473 286 ##STR00194##
1-(6-(5-(1-methyl-1H-pyrazol- 4-yl)-1H-pyrazolo[3,4-c]pyridin-
3-yl)pyridin-2-yl)-3- (trifluoromethyl)pyrrolidin-3-amine 0.000093
287 ##STR00195## (R)-1-(3-bromo-6-(5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)pyrrolidin-3-amine
0.000118 288 ##STR00196## 1-(3-methyl-6-(5-(pyridin-3-yl)-
1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-4-ol
0.000086 289 ##STR00197## (S)-1-(3-bromo-6-(5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-amine
0.000017 290 ##STR00198## (R)-1-(3-bromo-6-(5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-amine
0.000082 291 ##STR00199## (R)-1-(3-bromo-6-(5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin- 3-yl)pyridin-2-yl)piperidin-3-ol
0.000261 292 ##STR00200## 1-(3-bromo-6-(5-(pyridin-3-yl)-
1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-4-ol
0.000181 293 ##STR00201## (R)-1-(3-bromo-6-(5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin- 3-yl)pyridin-2-yl)pyrrolidin-3-ol
0.000412 294 ##STR00202## 1-(6-(5-(1-methyl-1H-pyrazol-4-
yl)-1H-pyrazolo[3,4-c]pyridin- 3-yl)pyridin-2-yl)piperidin-4-ol
0.000168 295 ##STR00203## 2-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)- 2,8-diazaspiro[4.5]decan-1-one 0.0399
296 ##STR00204## 1-(piperidin-4-ylmethyl)-3-(5-(pyridin-
3-yl)-1H-pyrazolo[3,4-c]pyridin- 3-yl)imidazolidin-2-one 0.00974
297 ##STR00205## 2-mcthyl-1-(6-(5-1-methyl-1H- pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-ylamino)propan-2-ol 0.000034
298 ##STR00206## (S)-1-(3-(6-(3-aminopipcridin-1-
yl)pyridin-2-yl)-1H- pyrazolo[3,4-c]pyridin-5-yl)urea 0.0141 299
##STR00207## (1S,3R)-3-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin- 2-yloxy)cyclohexanamine
0.000664 300 ##STR00208## (R)-1-(4-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyrimidin-2-yl)piperidin-3-amine
0.000070 301 ##STR00209## 1-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperazin-2-one 0.00295
302 ##STR00210## 2-(5-(pyridin-3-yl)-1H- pyrazolo[3,4-c]pyridin-3-
yl)isonicotinamide 0.0060 303 ##STR00211## 1-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)-3- (pyrrolidin-3-
ylmethyl)imidazolidin-2-one 0.00411 304 ##STR00212##
(S)-3-amino-1-(6-(5-(pyridin-3- yl)-1H-pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)pyrrolidin-2-one 0.000556 305 ##STR00213##
(S)-1-(3-methyl-6-(5-(pyridin-3- yl)-1H-pyrazolo[3,4-c]pyridin-
3-yl)pyridin-2-yl)pyrrolidin-3-ol 0.000091 306 ##STR00214##
(R)-1-(3-mcthyl-6-(5-(pyridin-3- yl)-1H-pyrazolo[3,4-c]pyridin-
3-yl)pyridin-2-yl)pyrrolidin-3-ol 0.00022 307 ##STR00215##
(S)-1-(6-(5-(pyridin-3-yl)-1H- pyrazolo[3,4-c]pyridin-3-yl)-3-
vinylpyridin-2-yl)piperidin-3-amine 0.000014 308 ##STR00216##
(S)-1-(3-(prop-1-en-2-yl)-6-(5- (pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-aminc
0.000010 309 ##STR00217## (R)-1-(3-methyl-6-(5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin- 3-yl)pyridin-2-yl)piperidin-3-ol
0.000112 310 ##STR00218## (R)-1-(3-methyl-6-(5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-aminc
0.000137 311 ##STR00219## (R)-1-(3-methyl-6-(5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)azepan-4-amine
0.000030 312 ##STR00220## (S)-1-(3-bromo-6-(5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)azepan-4-amine
0.000029 313 ##STR00221## (R)-1-(3-bromo-6-(5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)azepan-4-amine
0.000028 314 ##STR00222## (S)-1-(3-methyl-6-(5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)azepan-4-amine
0.000025 315 ##STR00223## (S)-1-(3-methyl-6-(5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-amine
0.00000806 316 ##STR00224## (R)-1-(3-methyl-6-(5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)pyrrolidin-3-amine
0.0000549 317 ##STR00225## (S)-1-(3-methyl-6-(5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)pyrrolidin-3-amine
0.000059 318 ##STR00226## (S)-1-(3-bromo-6-(5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)pyrrolidin-3-ol
0.000059 319 ##STR00227## (1-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin-
2-yl)piperidin-3-yl)methanamine 320 ##STR00228##
3-(3-(piperazin-1-yl)pyrrolidin-1- yl)-5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridine 0.00386 321 ##STR00229##
(3S,5R)-5-fluoro-1-(6-(5-(pyridin-
3-yl)-1H-pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)piperidin-3-amine 0.0000662 322 ##STR00230##
4-(6-(5-(pyridin-3-yl)-1H- pyrazolo[3,4-c]pyridin-3-yl)pyridin-
2-yl)-1,4-diazepan-2-one 0.000322 323 ##STR00231## 5-(3-phenyl-1H-
pyrazolo[3,4-c]pyridin-5-yl)thiazole 0.0330.033 324 ##STR00232##
(1-(6-(5-(pyridin-3-yl)-1H- pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)piperidin-2- yl)mcthanaminc 0.000296 325
##STR00233## 3-(4-aminopiperidine-1-carbonyl)-
1-(5-(pyridin-3-yl)-1H- pyrazolo[3,4-c]pyridin-3-
yl)pyrrolidin-2-one 0.106 326 ##STR00234##
N-(2-aminoethyl)-6-(5-(pyridin-3- yl)-1H-pyrazolo[3,4-c]pyridin-3-
yl)picolinamide 0.0177 327 ##STR00235##
(S)-1-(3-ethyl-6-(5-(pyridin-3- yl)-1H-pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)piperidin-3-amine 0.000035 328 ##STR00236##
(S)-1-(3-isopropyl-6-(5-(pyridin-
3-yl)-1H-pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)piperidin-3-amine 0.000046 329 ##STR00237##
N-(azetidin-3-yl)-6-(5-(pyridin- 3-yl)-1H-pyrazolo[3,4-c]pyridin-
3-yl)picolinamide 0.0165 330 ##STR00238## 1-methyl-4-(3-phenyl-1H-
pyrazolo[3,4-c]pyridin-5- yl)piperazin-2-one 0.66 331 ##STR00239##
1-methyl-4-(3-(1-methyl-1H- pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-5- yl)piperazin-2-one 0.721
332 ##STR00240## 5-(1-methyl-1H-pyrazol-4-yl)-3- (pyridin-2-yl)-1H-
pyrazolo[3,4-c]pyridine 0.00771 333 ##STR00241##
2-(1-(6-(5-(pyridin-3-yl)-1H- pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)pyrrolidin-3- yl)cthanaminc 0.00013 334
##STR00242## (S)-3-amino-1-(6-(5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin- 3-yl)pyridin-3-yl)pyrrolidin-2-one
0.00157 335 ##STR00243## 4-(3-(6-(piperazin-1-yl)pyridin-2-
yl)-1H-pyrazolo[3,4-c]pyridin- 5-yl)piperazin-2-one 0.0126 336
##STR00244## (4-aminopiperidin-1-yl)(6-(5- (pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin- 2-yl)methanone 0.0127 337
##STR00245## N-(piperidin-4-yl)-6-(5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)picolinamide 0.0305 338
##STR00246## 5-(3-(pyridin-2-yl)-1H-
pyrazolo[3,4-c]pyridin-5-yl)thiazole 0.0245 339 ##STR00247##
4-(3-(2-fluorophenyl)-1H- pyrazolo[3,4-c]pyridin-5-yl)-1-
methylpiperazin-2-one 5.5 340 ##STR00248##
(1R,3S)-N1-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin- 2-yl)cyclohexane-1,3-diamine
0.000044 341 ##STR00249## (1S,3R)-N1-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin- 2-yl)cyclohexane-1,3-diamine
0.000077 342 ##STR00250## (S)-1-(3-ethynyl-6-(5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-amine
0.0000100 343 ##STR00251## (S)-3-methyl-1-(6-(5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-amine
0.000045 344 ##STR00252## (S)-1-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin- 3-yl)pyrrolidine-2-carboxamide
0.0039 345 ##STR00253## (S)-4-(3-(6-(3-aminopiperidin-1-
yl)pyridin-2-yl)-1H- pyrazolo[3,4-c]pyridin-5- yl)piperazin-2-one
0.0137 346 ##STR00254## 1-(3-(6-(piperazin-1-yl)pyridin-2-
yl)-1H-pyrazolo[3,4-c]pyridin-5- yl)piperazin-2-one 0.219 347
##STR00255## (R)-3-methyl-1-(6-(5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-amine
0.00011 348 ##STR00256## 5-(3-(2-fluorophenyl)-1H-
pyrazolo[3,4-c]pyridin-5-yl)thiazole 0.0268 349 ##STR00257##
(S)-1-(6-(5-(thiazol-5-yl)-1H- pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)piperidin-3-amine 0.000035 350 ##STR00258##
(R)-1-(6-(5-(thiazol-5-yl)-1H- pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)piperidin-3-amine 0.000036 351 ##STR00259##
1-methyl-4-(3-(pyridin-2-yl)-1H- pyrazolo[3,4-c]pyridin-5-
yl)piperazin-2-one 4.8 352 ##STR00260##
(1R,3R)-N1-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin- 2-yl)cyclohexane-1,3-diamine
0.000025 353 ##STR00261## (1S,3S)-N1-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin- 2-yl)cyclohexane-1,3-diamine
0.000397 354 ##STR00262## 2-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)-5- (trifluoromethyl)pyridine 1-oxide
0.0979 355 ##STR00263## 3-methyl-1-(3-phenyl-1H-
pyrazolo[3,4-c]pyridin-5- yl)imidazolidine-2,4-dione 0.809 356
##STR00264## 5-(1-ethyl-1H-pyrazol-4-yl)-3-
(6-(piperazin-1-yl)pyridin-2-yl)- 1H-pyrazolo[3,4-c]pyridine
0.000073 357 ##STR00265## 2-(4-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)-1,4-diazepan-1-
yl)ethanol 0.00026 358 ##STR00266##
5-(3-(6-(piperidin-1-yl)pyridin- 2-yl)-1H-pyrazolo[3,4-c]pyridin-
5-yl)thiazole 0.00122 359 ##STR00267##
5-(3-(6-(piperazin-1-yl)pyridin- 2-yl)-1H-pyrazolo[3,4-c]pyridin-
5-yl)thiazole 0.000074 360 ##STR00268##
5-(1-methyl-1H-pyrazol-4-yl)-3- (2-(piperidin-1-yl)pyrimidin-4-
yl)-1H-pyrazolo[3,4-c]pyridine 0.000366 361 ##STR00269##
5-(1-methyl-1H-pyrazol-4-yl)-3- (2-(piperazin-1-yl)pyrimidin-4-
yl)-1H-pyrazolo[3,4-c]pyridine 362 ##STR00270##
(S)-1-(3-butyl-6-(5-(pyridin-3- yl)-1H-pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)piperidin-3-amine 0.000079 363 ##STR00271##
5-(1H-imidazol-1-yl)-3-(6- (piperidin-1-yl)pyridin-2-yl)-
1H-pyrazolo[3,4-c]pyridine 0.00241 364 ##STR00272##
(R)-1-(4-(5-(1-methyl-1H-pyrazol-
4-yl)-1H-pyrazolo[3,4-c]pyridin-3-
yl)pyrimidin-2-yl)piperidin-3-amine 0.000052 365 ##STR00273##
(S)-1-(4-(5-(1-methyl-1H-pyrazol-
4-yl)-1H-pyrazolo[3,4-c]pyridin-3-
yl)pyrimidin-2-yl)pipcridin-3-amine 0.0000941 366 ##STR00274##
1-methyl-4-(3-(6-(piperazin-1- yl)pyridin-2-yl)-1H-
pyrazolo[3,4-c]pyridin-5- yl)pyridin-2(1H)-one 0.00097 367
##STR00275## 5-(6-methylpyridin-3-yl)-3-(6-
(piperazin-1-yl)pyridin-2-yl)- 1H-pyrazolo[3,4-c]pyridine 0.000217
368 ##STR00276## 5-(1H-imidazol-1-yl)-3-(6-
(piperazin-1-yl)pyridin-2-yl)- 1H-pyrazolo[3,4-c]pyridine 0.00182
369 ##STR00277## (R)-1-(6-(5-(1H-imidazol-1-yl)-
1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-amine
0.00113 370 ##STR00278## (R)-3-(3-(6-(3-aminopiperidin-
1-yl)pyridin-2-yl)-1H- pyrazolo[3,4-c]pyridin-5-
yl)oxazolidin-2-one 0.18 371 ##STR00279##
3-methyl-1-(3-(6-(piperazin-1- yl)pyridin-2-yl)-1H-
pyrazolo[3,4-c]pyridin-5- yl)imidazolidine-2,4-dione 0.0311 372
##STR00280## 5-(1-ethyl-1H-pyrazol-4-yl)-3-(6-
(4-methylpiperazin-1-yl)pyridin-2- yl)-1H-pyrazolo[3,4-c]pyridine
0.000268 373 ##STR00281## 3-(3-(6-(piperidin-1-yl)pyridin-2-yl)-
1H-pyrazolo[3,4-c]pyridin-5- yl)oxazolidin-2-one 0.483 374
##STR00282## (S)-3-(3-(6-(3-aminopiperidin-1- yl)pyridin-2-yl)-1H-
pyrazolo[3,4-c]pyridin-5- yl)oxazolidin-2-one 0.085 375
##STR00283## 3-(6-(piperazin-1-yl)pyridin-2-
yl)-5-(1-propyl-1H-pyrazol-4- yl)-1H-pyrazolo[3,4-c]pyridine
0.000039 376 ##STR00284## (S)-1-(3-bromo-6-(5-(1-methyl-
1H-pyrazol-4-yl)-1H- pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)piperidin-3-amine 0.0000090 377 ##STR00285##
(S)-1-(6-(5-(1-ethyl-1H-pyrazol- 4-yl)-1H-pyrazolo[3,4-c]pyridin-
3-yl)pyridin-2-yl)-N- methylpiperidin-3-amine 0.000080 378
##STR00286## 5-(6-fluoropyridin-3-yl)-3-(6-
(piperazin-1-yl)pyridin-2-yl)- 1H-pyrazolo[3,4-c]pyridine 0.000796
379 ##STR00287## 1-(3-amino-2,2-dimethylpropyl)-
5-(5-(pyridin-3-yl)-1H- pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2(1H)-one 0.00129 380 ##STR00288##
(S)-1-(6-(5-(1H-imidazol-1-yl)- 1H-pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)piperidin-3-amine 0.000523 381 ##STR00289##
5-(1-isobutyl-1H-pyrazol-4-yl)- 3-(6-(piperazin-1-yl)pyridin-2-
yl)-1H-pyrazolo[3,4-c]pyridine 0.000057 382 ##STR00290##
5-(1-(2-methoxyethyl)-1H- pyrazol-4-yl)-3-(6-
(piperazin-1-yl)pyridin-2-yl)- 1H-pyrazolo[3,4-c]pyridine 0.000060
383 ##STR00291## 3-methyl-1-(6-(5-(1-methyl-1H- pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-ol 0.000078
384 ##STR00292## 5-(5-methylpyridin-3-yl)-3-(6-
(piperazin-1-yl)pyridin-2-yl)- 1H-pyrazolo[3,4-c]pyridine 0.000041
385 ##STR00293## (3S,5R)-1-(6-(5-(1-ethyl- 1H-pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)-5-
fluoropiperidin-3-amine 0.000131 386 ##STR00294##
(S)-1-(6-(5-(pyridin-3-yl)-1H- pyrazolo[3,4-c]pyridin-3-yl)-3-
(trifluoromethyl)pyridin-2- yl)piperidin-3-amine 0.000117 387
##STR00295## 4-(1-(3-bromo-6-(5-(1-methyl- 1H-pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)azetidin-3-
yl)-1,1-dioxothiomorpholine 0.00159 388 ##STR00296##
2-methyl-1-(4-(3-(6-(piperazin- 1-yl)pyridin-2-yl)-1H-
pyrazolo[3,4-c]pyridin-5-yl)- 1H-pyrazol-1-yl)propan-2-ol 0.000138
389 ##STR00297## 5-(1-isopropyl-1H-pyrazol-4-yl)-
3-(6-(piperazin-1-yl)pyridin-2- yl)-1H-pyrazolo[3,4-c]pyridine
0.000213 390 ##STR00298## 5-(1-cyclobutyl-1H-pyrazol-4-
yl)-3-(6-(piperazin-1-yl)pyridin- 2-yl)-1H-pyrazolo[3,4-c]pyridine
0.000132 391 ##STR00299## 5-(1-(2-fluoroethyl)-1H-pyrazol-
4-yl)-3-(6-(piperazin-1-yl)pyridin-
2-yl)-1H-pyrazolo[3,4-c]pyridine 0.000108 392 ##STR00300##
1-(3-bromo-6-(5-(1-methyl-1H- pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-4-aminc
0.000030 393 ##STR00301## (S)-1-(3-bromo-6-(5-(1-methyl-
1H-pyrazol-4-yl)-1H- pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)piperidin-3-ol 0.000333 394 ##STR00302##
(R)-1-(3-bromo-6-(5-(1-methyl- 1H-pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-ol 0.000316
395 ##STR00303## 5-(1-ethyl-1H-pyrazol-4-yl)-3-(6- ((3aR,6aS)-
hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)pyridin-2-yl)-1H-
pyrazolo[3,4-c]pyridine 0.000404 396 ##STR00304##
(S)-5-(1-ethyl-1H-pyrazol-4-yl)- 3-(6-(3-methylpiperazin-1-
yl)pyridin-2-yl)-1H- pyrazolo[3,4-c]pyridine 0.000081 397
##STR00305## (R)-5-(1-ethyl-1H-pyrazol-4-yl)-
3-(6-(3-methylpiperazin-1- yl)pyridin-2-yl)-1H-
pyrazolo[3,4-c]pyridine 0.000046 398 ##STR00306##
(R)-3-(6-(3-aminopiperidin-1- yl)pyridin-2-yl)-1H-
pyrazolo[3,4-c]pyridine-5- carbonitrile 0.0391 399 ##STR00307##
(S)-3-(6-(3-aminopiperidin-1- yl)pyridin-2-yl)-1H-
pyrazolo[3,4-c]pyridine-5- carbonitrile 0.0226 400 ##STR00308##
3-(6-(piperazin-1-yl)pyridin-2- yl)-1H-pyrazolo[3,4-c]pyridine-
5-carbonitrile 0.0511 401 ##STR00309##
4-(3-(6-(piperazin-1-yl)pyridin- 2-yl)-1H-pyrazolo[3,4-c]pyridin-
5-yl)morpholine 0.00329 402 ##STR00310##
3-(5-bromo-6-(4-methylpiperazin- 1-yl)pyridin-2-yl)-5-(1-methyl-
1H-pyrazol-4-yl)-1H- pyrazolo[3,4-c]pyridine 0.000070 403
##STR00311## (S)-1-(3-bromo-6-(5-(1-ethyl- 1H-pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-amine
0.000040 404 ##STR00312## 3-(5-bromo-6-(piperazin-1-
yl)pyridin-2-yl)-5-(1-ethyl-1H- pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridine 0.000090 405 ##STR00313##
4-(1-(3-bromo-6-(5-(1-methyl-1H- pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)azetidin-3-
yl)piperazin-2-one 0.000527 406 ##STR00314##
3-(5-bromo-6-(3,3-dimcthyl-4-(2- (methylsulfonyl)ethyl)piperazin-
1-yl)pyridin-2-yl)-5-(1-methyl- 1H-pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridinc 0.000259
407 ##STR00315## (R)-1-(3-bromo-6-(5-(1-ethyl- 1H-pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-amine 408
##STR00316## 4-(1-(3-bromo-6-(5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)azetidin-3-
yl)piperazin-2-one 409 ##STR00317##
3-(6-(1,4-diazepan-1-yl)pyridin-2-
yl)-5-(1-ethyl-1H-pyrazol-4-yl)-1H- pyrazolo[3,4-c]pyridine
0.000020 410 ##STR00318## (S)-1-(6-(5-(1-ethyl-1H-pyrazol-4-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)-1,4-diazepan-6-ol
0.000039 411 ##STR00319## (R)-1-(6-(5-(1-ethyl-1H-pyrazol-4-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)-1,4-diazepan-6-ol
0.000014 412 ##STR00320## (S)-1-(6-(5-(1-methyl-1H-pyrazol-
4-yl)-1H- pyrazolo[3,4-c]pyridin-3-yl)-3-
vinylpyridin-2-yl)piperidin-3-amine 0.000036 413 ##STR00321##
4-(1-(3-methyl-6-(5-(1-methyl-1H- pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)azetidin-3-yl)-
1,1-dioxothiomorpholine 0.00102 414 ##STR00322##
(S)-1-(6-(5-(1-methyl-1H-pyrazol-4-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)-3-(prop-1-en-2-yl)pyridin-2-
yl)piperidin-3-amine 0.000028 415 ##STR00323##
3-(3-(6-(piperazin-1-yl)pyridin-2- yl)-1H-pyrazolo[3,4-c]pyridin-5-
yl)oxazolidin-2-one 0.104 416 ##STR00324##
5-(1-(oxetan-3-ylmethyl)-1H- pyrazol-4-yl)-3-(6-(piperazin-1-
yl)pyridin-2-yl)-1H- pyrazolo[3,4-c]pyridine 0.0113 417
##STR00325## 1-(3-methyl-6-(5-(1-methyl-1H- pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin- 2-yl)piperidin-4-amine
0.000051 418 ##STR00326## (R)-1-(3-methyl-6-(5-(1-mcthyl-1H-
pyrazol-4-yl)-1H- pyrazolo[3,4-c]pyridin-3-yl)pyridin-
2-yl)piperidin-3-ol 0.00011 419 ##STR00327##
4-(3-methyl-6-(5-(1-methyl-1H- pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin- 2-yl)morpholine 0.00016 420
##STR00328## 4-(6-(5-(1-methyl-1H-pyrazol-4-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)morpholine
0.000368 421 ##STR00329## 3-(6-(4-fluoropiperidin-4-
yl)pyridin-2-yl)-5-(pyridin-3-yl)- 1H-pyrazolo[3,4-c]pyridine
0.000105 422 ##STR00330## 4-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-4-ol 0.000684
423 ##STR00331## (S)-3-methyl-1-(6-(5-(1-methyl-
1H-pyrazol-4-yl)-1H- pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)piperidin-3-ol 0.000128 424 ##STR00332##
(R)-3-methyl-1-(6-(5-(1-methyl- 1H-pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-ol 0.000073
425 ##STR00333## 4-(1-(3-methyl-6-(5-(1-methyl-1H-
pyrazol-4-yl)-1H- pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)azetidin-3- yl)piperazin-2-one 0.000618 426
##STR00334## 4-(1-(3-methyl-6-(5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)azetidin-3-
yl)piperazin-2-one 0.00046 427 ##STR00335##
(S)-1-(6-(5-(1-ethyl-1H-pyrazol- 4-yl)-1H-pyrazolo[3,4-c]pyridin-
3-yl)-3-(prop-1-en-2-yl)pyridin- 2-yl)piperidin-3-amine 0.000016
428 ##STR00336## 3-(6-(3,3-dimethyl-4-(2-
(methylsulfonyl)ethyl)piperazin- 1-yl)-5-methylpyridin-2-yl)-5-
(1-methyl-1H-pyrazol-4-yl)-1H- pyrazolo[3,4-c]pyridine 0.000112 429
##STR00337## (S)-1-(3-ethyl-6-(5-(1-methyl-1H- pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin- 2-yl)piperidin-3-amine
0.000022 430 ##STR00338## (S)-1-(6-(5-(1-ethyl-1H-pyrazol-
4-yl)-1H-pyrazolo[3,4-c]pyridin- 3-yl)-3-methylpyridin-2-
yl)piperidin-3-amine 0.000027 431 ##STR00339##
(S)-1-(6-(5-(1-ethyl-1H-pyrazol- 4-yl)-1H-pyrazolo[3,4-c]pyridin-
3-yl)-3-vinylpyridin-2- yl)piperidin-3-amine 0.000023 432
##STR00340## 5-(1-cthyl-1H-pyrazol-4-yl)-3-(5-
methyl-6-(piperazin-1-yl)pyridin- 2-yl)-1H-pyrazolo[3,4-c]pyridine
0.000055 433 ##STR00341## (S)-1-(3-methyl-6-(5-(1-mcthyl-1H-
pyrazol-4-yl)-1H- pyrazolo[3,4-c]pyridin-3-yl)pyridin-
2-yl)piperidin-3-amine 0.000013 434 ##STR00342##
(S)-1-(3-isopropyl-6-(5-(1-methyl- 1H-pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin- 2-yl)piperidin-3-amine 435
##STR00343## 4-fluoro-1-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-ol 0.000089
436 ##STR00344## 5-(5-methoxypyridin-3-yl)-3-(6-
(piperazin-1-yl)pyridin-2-yl)-1H- pyrazolo[3,4-c]pyridine 0.000021
437 ##STR00345## N-methyl-6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-amine 0.000409 438
##STR00346## 5-(5-ethylpyridin-3-yl)-3-(6-
(piperazin-1-yl)pyridin-2-yl)- 1H-pyrazolo[3,4-c]pyridine 0.0000040
439 ##STR00347## 5-(1-methyl-1H-pyrazol-4-yl)-3-
(2-(piperidin-4-yl)pyrimidin-4- yl)-1H-pyrazolo[3,4-c]pyridine
0.000571 440 ##STR00348## 5-(1-methyl-1H-pyrazol-4-yl)-3-(5-
methyl-6-(4-methylpiperazin-1- yl)pyridin-2-yl)-1H-
pyrazolo[3,4-c]pyridine 0.000029 441 ##STR00349##
(S)-1-(3-methyl-6-(5-(1-methyl-1H- pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-ol 0.000062
442 ##STR00350## (S)-1-(6-(5-(1-methyl-1H-pyrazol-
4-yl)-1H-pyrazolo[3,4-c]pyridin- 3-yl)pyridin-2-yl)piperidin-3-ol
0.000154 443 ##STR00351## (R)-1-(6-(5-(1-ethyl-1H-pyrazol-
4-yl)-1H-pyrazolo[3,4-c]pyridin- 3-yl)-3-methylpyridin-2-
yl)pipcridin-3-aminc 0.00010 444 ##STR00352## 3-(6-((3S,5R)-3,5-
dimethylpiperazin-1-yl)pyridin- 2-yl)-5-(1-ethyl-1H-pyrazol-4-
yl)-1H-pyrazolo[3,4-c]pyridine 0.000070 445 ##STR00353##
(S)-1-(6-(5-(1-ethyl-1H-pyrazol-4- yl)-1H-pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)piperidin-3-amine 0.000031 446 ##STR00354##
3-(6-(3,3-dimethylpiperazin-1- yl)pyridin-2-yl)-5-(1-ethyl-1H-
pyrazol-4-yl)-1H- pyrazolo[3,4-c]pyridine 0.000029 447 ##STR00355##
3-(6-(6,6-difluoro-1,4-diazepan-1- yl)pyridin-2-yl)-5-(1-ethyl-1H-
pyrazol-4-yl)-1H- pyrazolo[3,4-c]pyridine 0.000029 448 ##STR00356##
5-(1-tert-butyl-1H-pyrazol-4-yl)- 3-(6-(piperazin-1-yl)pyridin-2-
yl)-1H-pyrazolo[3,4-c]pyridine 0.000376 449 ##STR00357##
4-(3-bromo-6-(5-(1-methyl-1H- pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)morpholine 0.000191 450
##STR00358## 4-(6-(5-(1-ethyl-1H-pyrazol-4-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)morpholine
0.000581 451 ##STR00359## (R)-1-(6-(5-(1-methyl-1H-pyrazol-
4-yl)-1H-pyrazolo[3,4-c]pyridin- 3-yl)pyridin-2-yl)piperidin-3-ol
0.000106 452 ##STR00360## cis-4-fluoro-1-(6-(5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-amine
0.000046 453 ##STR00361## trans-4-fluoro-1-(6-(5-(pyridin-3-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-amine
0.000296 454 ##STR00362## (3S,5R)-1-(3-bromo-6-(5-(1-ethyl-
1H-pyrazol-4-yl)-1H- pyrazolo[3,4-c]pyridin-3-yl)pyridin-
2-yl)-5-fluoropiperidin-3-amine 0.000026 455 ##STR00363##
(3R,5R)-1-(3-bromo-6-(5-(1-ethyl- 1H-pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin-
2-yl)-5-fluoropiperidin-3-amine 0.000028 456 ##STR00364##
(3S,5R)-1-(3-bromo-6-(5-(1-methyl- 1H-pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin-
2-yl)-5-fluoropiperidin-3-amine 0.000030 457 ##STR00365##
3-(6-(1,4-diazepan-1-yl)-4- methylpyridin-2-yl)-5-(1-ethyl-
1H-pyrazol-4-yl)-1H- pyrazolo[3,4-c]pyridine 0.000049 458
##STR00366## (1R)-3-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)cyclohexanamine 0.000030
459 ##STR00367## (1S)-3-(6-(5-(pyridin-3-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)cyclohexanamine 0.000045
460 ##STR00368## (R)-1-(6-(5-(1-ethyl-1H-pyrazol-
4-yl)-1H-pyrazolo[3,4-c]pyridin- 3-yl)pyridin-2-yl)-3-
methylpiperidin-3-ol 0.000265 461 ##STR00369##
N1-(6-(5-(1-ethyl-1H-pyrazol-4- yl)-1H-pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)cyclohexane-1,3- diamine 0.0000593 462 ##STR00370##
trans-1-(6-(5-(1-ethyl-1H-pyrazol-
4-yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)-4-
fluoropiperidin-3-amine 0.00055 463 ##STR00371##
(4-(6-(5-(1-ethyl-1H-pyrazol-4- yl)-1H-pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)piperazin-2- yl)methanol 0.000084 464 ##STR00372##
(S)-1-(6-(5-(1-ethyl-1H-pyrazol- 4-yl)-1H-pyrazolo[3,4-c]pyridin-
3-yl)pyridine-2-yl)-3- methylpiperidin-3-ol 0.0000721 465
##STR00373## cis-1-(6-(5-(1-ethyl-1H-pyrazol-
4-yl)-1H-pyrazolo[3,4-c]pyridin- 3-yl)pyridin-2-yl)-4-
fluoropiperidin-3-amine 0.000063 466 ##STR00374##
(S)-1-(5-chloro-6-(5-(1-ethyl-1H- pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin- 2-yl)piperidin-3-amine
0.000389 467 ##STR00375## 3-(6-(piperazin-1-yl)pyridin-2-
yl)-5-(5-(trifluoromethyl)pyridin- 3-yl)-1H-pyrazolo[3,4-c]pyridine
0.000093 468 ##STR00376## 5-(1-ethyl-1H-pyrazol-4-yl)-3-(6-
(3-(trifluoromethyl)piperazin-1- yl)pyridin-2-yl)-1H-
pyrazolo[3,4-c]pyridine 0.000060 469 ##STR00377##
5-(1-ethyl-1H-pyrazol-4-yl)-3-(4- (trifluoromethyl)pyridin-2-yl)-
1H-pyrazolo[3,4-c]pyridine 0.0656 470 ##STR00378##
5-(5-(methylsulfonyl)pyridin-3-yl)-
3-(6-(piperazin-1-yl)pyridin-2-yl)- 1H-pyrazolo[3,4-c]pyridine
0.000049 471 ##STR00379## (R)-1-(6-(5-(1-ethyl-1H-pyrazol-
4-yl)-1H-pyrazolo[3,4-c]pyridin- 3-yl)pyridin-2-yl)azepan-4-amine
0.000073 472 ##STR00380## 1-(4-(6-(5-(1-ethyl-1H-pyrazol-4-
yl)-1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperazin-1-
yl)ethanone 0.000107 473 ##STR00381##
2-(4-(3-(6-(piperazin-1-yl)pyridin-
2-yl)-1H-pyrazolo[3,4-c]pyridin- 5-yl)-1H-pyrazol-1-yl)acetonitrile
0.000022 474 ##STR00382## 1-((5-(5-(1-ethyl-1H-pyrazol-4-yl)-
1H-pyrazolo[3,4-c]pyridin-3-yl)-2- oxopyridin-1(2H)-
yl)methyl)cyclopropanecarboxamide 0.00141 475 ##STR00383##
1-((5-(5-(1-ethyl-1H-pyrazol-4- yl)-1H-pyrazolo[3,4-c]pyridin-3-
yl)-2-oxopyridin-1(2H)- yl)methyl)cyclobutanecarboxamide 0.00449
476 ##STR00384## 5-(1-ethyl-1H-pyrazol-4-yl)-3-
(4-methoxypyridin-2-yl)-1H- pyrazolo[3,4-c]pyridine 0.0157
477 ##STR00385## (S)-1-(3-ethyl-6-(5-(1-ethyl-1H- pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)piperidin-3-amine
0.000013 478 ##STR00386## (S)-1-(6-(5-(1-ethyl-1H-pyrazol-
4-yl)-1H-pyrazolo[3,4-c]pyridin- 3-yl)-3-isopropylpyridin-2-
yl)piperidin-3-amine 0.000020 479 ##STR00387##
5-(1-ethyl-1H-pyrazol-4-yl)-3-(6- (piperazin-1-yl)pyrazin-2-yl)-1H-
pyrazolo[3,4-c]pyridine 0.000064 480 ##STR00388##
5-(1-ethyl-1H-pyrazol-4-yl)-3- (6-(4-(oxetan-3-yl)piperazin-1-
yl)pyridin-2-yl)-1H- pyrazolo[3,4-c]pyridine 0.000311 481
##STR00389## (S)-1-(6-(5-(1-ethyl-1H-pyrazol-
4-yl)-1H-pyrazolo[3,4-c]pyridin- 3-yl)pyridin-2-yl)azepan-4-amine
0.000034 482 ##STR00390## (R)-1-(6-(5-(1-ethyl-1H-pyrazol-
4-yl)-1H-pyrazolo[3,4-c]pyridin- 3-yl)pyridin-2-yl)-N-
methylpiperidin-3-amine 0.000147 483 ##STR00391##
1-(5-(3-(6-(piperazin-1-yl)pyridin-
2-yl)-1H-pyrazolo[3,4-c]pyridin- 5-yl)pyridin-3-yl)ethanol 0.000027
484 ##STR00392## 3-(4-cyclopropylpyridin-2-yl)-5-
(1-ethyl-1H-pyrazol-4-yl)-1H- pyrazolo[3,4-c]pyridine 0.0115 485
##STR00393## (S)-1-(3-cyclopropyl-6-(5-(pyridin-
3-yl)-1H-pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)piperidin-3-amine 0.000022 486 ##STR00394##
(S)-1-(3-cyclopropyl-6-(5-(1-methyl- 1H-pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin- 2-yl)piperidin-3-amine
0.0000090 487 ##STR00395## 5-(1-cyclopropyl-1H-pyrazol-4-yl)-
3-(6-(pipcrazin-1-yl)pyridin-2-yl)- 1H-pyrazolo[3,4-c]pyridine
0.000106 488 ##STR00396## 3-(6-(piperazin-1-yl)pyridin-2-yl)-5-
(1-(2,2,2-trifluoroethyl)-1H-pyrazol-
4-yl)-1H-pyrazolo[3,4-c]pyridine 0.000022 489 ##STR00397##
3-(6-(1,4-diazcpan-1-yl)pyridin-2-
yl)-5-(1-(2-fluoroethyl)-1H-pyrazol-
4-yl)-1H-pyrazolo[3,4-c]pyridine 0.000014 490 ##STR00398##
2-(1,4-diazepan-1-yl)-6-(5-(1-ethyl- 1H-pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3- yl)isonicotinonitrile 0.000107 491
##STR00399## 5-(1-cthyl-1H-pyrazol-4-yl)-3-(6-(5-
(trifluoromethyl)-1,4-diazepan-1- yl)pyridin-2-yl)-1H-
pyrazolo[3,4-c]pyridine 0.000181 492 ##STR00400##
5-(1-ethyl-1H-pyrazol-4-yl)-3-(4- methylpyridin-2-yl)-1H-
pyrazolo[3,4-c]pyridine 0.0232 493 ##STR00401##
5-(1-ethyl-1H-pyrazol-4-yl)-3-(4- ethylpyridin-2-yl)-1H-
pyrazolo[3,4-c]pyridine 0.0436 494 ##STR00402##
1-(6-(5-(1-ethyl-1H-pyrazol-4-yl)- 1H-pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)azepan-3-ol 0.000122 495 ##STR00403##
(3S,5R)-5-fluoro-1-(6-(5-(1-methyl- 1H-pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin- 2-yl)piperidin-3-amine
0.000122 496 ##STR00404## 2-(4-(3-(6-(piperazin-1-yl)pyridin-2-
yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)- 1H-pyrazol-1-yl)ethanol
0.00013 497 ##STR00405## 5-(1-(cyclopropylmethyl)-1H-
pyrazol-4-yl)-3-(6-(piperazin-1- yl)pyridin-2-yl)-1H-
pyrazolo[3,4-c]pyridine 0.000021 498 ##STR00406##
(2-(5-(1-ethyl-1H-pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin- 4-yl)methanol 0.0172 499
##STR00407## 1-(6-(5-(1-ethyl-1H-pyrazol-4-yl)-
1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)-1,4-diazepane-6-
carbonitrile 0.000072 500 ##STR00408##
5-(1-ethyl-1H-pyrazol-4-yl)-3-(4- (prop-1-en-2-yl)pyridin-2-yl)-1H-
pyrazolo[3,4-c]pyridine 0.0541 501 ##STR00409##
(S)-1-(6-(5-(1-ethyl-1H-pyrazol-4- yl)-1H-pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)azepan-3-ol 0.000103 502 ##STR00410##
(R)-1-(6-(5-(1-ethyl-1H-pyrazol-4- yl)-1H-pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)azepan-3-ol 0.000139 503 ##STR00411##
(S)-5-(1-(2-fluoroethyl)-1H-pyrazol-
4-yl)-3-(6-(3-methylpiperazin-1- yl)pyridin-2-yl)-1H-
pyrazolo[3,4-c]pyridine 0.0000294 504 ##STR00412##
5-(1-ethyl-1H-pyrazol-4-yl)-3-(6-
(6-fluoro-1,4-diazepan-1-yl)pyridin-
2-yl)-1H-pyrazolo[3,4-c]pyridine 0.000076 505 ##STR00413##
5-(6-methylpyrazin-2-yl)-3-(6- (piperazin-1-yl)pyridin-2-yl)-1H-
pyrazolo[3,4-c]pyridine 0.0000100 506 ##STR00414##
(S)-1-(3-cyclopropyl-6-(5-(1-ethyl- 1H-pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin- 2-yl)piperidin-3-amine
0.000021 507 ##STR00415## 5-(1-ethyl-1H-pyrazol-4-yl)-3-(4-
isopropylpyridin-2-yl)-1H- pyrazolo[3,4-c]pyridine 0.0298 508
##STR00416## 5-(1-ethyl-1H-pyrazol-4-yl)-3- (pyridin-2-yl)-1H-
pyrazolo[3,4-c]pyridine 0.0106 509 ##STR00417##
(3S,5R)-5-fluoro-1-(3-methyl-6-(5- (1-methyl-1H-pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin- 2-yl)piperidin-3-amine
0.000056 510 ##STR00418## (3S,5R)-1-(6-(5-(1-ethyl-1H-
pyrazol-4-yl)-1H- pyrazolo[3,4-c]pyridin-3-yl)-3-
methylpyridin-2-yl)-5- fluoropiperidin-3-amine 0.000030 511
##STR00419## (1-(6-(5-(1-ethyl-1H-pyrazol-4-yl)-
1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)-1,4-diazepan-6-
yl)methanol 0.000016 512 ##STR00420##
(1-(6-(5-(1-ethyl-1H-pyrazol-4-yl)- 1H-pyrazolo[3,4-c]pyridin-3-
yl)pyridin-2-yl)-1,4-diazepan-6- yl)methanol 0.000040 513
##STR00421## N-(6-(5-(1-ethyl-1H-pyrazol-4-yl)-
1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)azepan-3-amine
0.000055 514 ##STR00422## 1-(6-(5-(1-(2-fluoroethyl)-1H-
pyrazol-4-yl)-1H- pyrazolo[3,4-c]pyridin-3-yl)pyridin-
2-yl)azepan-3-amine 0.000077 515 ##STR00423##
3-ethyl-5-(3-(6-(piperazin-1- yl)pyridin-2-yl)-1H-
pyrazolo[3,4-c]pyridin-5- yl)pyrimidin-4(3H)-one 0.000015 516
##STR00424## 5-(1-(2-fluoroethyl)-1H-pyrazol-4-
yl)-3-(6-(3-methylpiperazin-1- yl)pyridin-2-yl)-1H-
pyrazolo[3,4-c]pyridine 0.000024 517 ##STR00425##
(3R,5R)-5-fluoro-1-(6-(5-(1-methyl- 1H-pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin- 2-yl)piperidin-3-amine 0.00117
518 ##STR00426## 1-(6-(5-(1-ethyl-1H-pyrazol-4-yl)-
1H-pyrazolo[3,4-c]pyridin-3- yl)pyridin-2-yl)azepan-3-amine
0.000082 519 ##STR00427## (S)-1-(6-(5-(1-(2-fluorocthyl)-1H-
pyrazol-4-yl)-1H- pyrazolo[3,4-c]pyridin-3-yl)pyridin-
2-yl)azepan-3-amine 0.000025 520 ##STR00428##
(R)-1-(6-(5-(1-(2-fluoroethyl)-1H- pyrazol-4-yl)-1H-
pyrazolo[3,4-c]pyridin-3-yl)pyridin- 2-yl)azepan-3-amine 0.000098
521 ##STR00429## (R)-5-(1-(2-fluoroethyl)-1H-pyrazol-
4-yl)-3-(6-(3-methylpiperazin-1- yl)pyridin-2-yl)-1H-
pyrazolo[3,4-c]pyridine 0.000026
TABLE-US-00002 TABLE 2 Pim-1 No. Structure Name Ki (.mu.m) 522
##STR00430## 3-(6-(1,4-diazepan-1- yl)pyridin-2-yl)-5-(6-
methylpyrazin-2-yl)-1H- pyrazolo[3,4- c]pyridine 0.000019 523
##STR00431## 3-(2,5-difluorophenyl)- 5-(1H-pyrazol-4-yl)-1H-
pyrazolo[3,4- c]pyridine 524 ##STR00432## 4-(3-(2-fluorophenyl)-
1H-pyrazolo[3,4- c]pyridin-5-yl)- 1H-pyrazol-3-amine 525
##STR00433## 3-(2-fluorophenyl)- 5-(3-(trifluoromethyl)-
1H-pyrazol-4-yl)-1H- pyrazolo[3,4- c]pyridine 526 ##STR00434##
3-(2-fluorophenyl)- 5-(5-methyl-1H- pyrazol-4-yl)-1H- pyrazolo[3,4-
c]pyridine 527 ##STR00435## 2-(5-(1H-pyrazol- 4-yl)-1H-
pyrazolo[3,4- c]pyridin-3-yl)-3- fluoroaniline
[0084] The compounds of the present invention were tested for their
capacity to inhibit Pim kinase activity and for their biological
effects on growing cells as described below in Examples 901 and
902. Formula I compounds having Ki/IC.sub.50/EC.sub.50 of less than
1 .mu.M in assays described in Examples 901 and 902, may be useful
therapeutically as Pim kinase inhibitors (Pim-1, Pim-2 and/or
Pim-3).
[0085] The present invention includes a composition (e.g., a
pharmaceutical composition) comprising a compound of Formula I,
and/or solvates, hydrates and/or salts thereof, and a carrier (a
pharmaceutically acceptable carrier). The present invention also
includes a composition (e.g., a pharmaceutical composition)
comprising a compound of Formula I and/or solvates, hydrates and/or
salts thereof, and a carrier (a pharmaceutically acceptable
carrier), further comprising a second chemotherapeutic agent such
as those described herein. The present compositions are useful for
inhibiting abnormal cell growth or treating a hyperproliferative
disorder such as cancer in a mammal (e.g., human). For example, the
present compounds and compositions are useful for treating multiple
myeloma, lymphoma, acute myeloid leukemia, prostate cancer, breast
cancer, hepatocellular carcinoma, pancreatic cancer, and/or
colorectal cancer in a mammal (e.g., human).
[0086] The present invention includes a method of inhibiting
abnormal cell growth or treating a hyperproliferative disorder such
as cancer in a mammal (e.g., human) comprising administering to
said mammal a therapeutically effective amount of a compound of
Formula I, and/or solvates, hydrates and/or salts thereof, or a
composition thereof. For example, the present invention includes a
method of treating multiple myeloma, lymphoma, acute myeloid
leukemia, prostate cancer, breast cancer, hepatocellular carcinoma,
pancreatic cancer, and/or colorectal cancer in a mammal (e.g.,
human), comprising administering to said mammal a therapeutically
effective amount of a compound of Formula I, and/or solvates,
hydrates and/or salts thereof) or a composition thereof.
[0087] The present invention includes a method of inhibiting
abnormal cell growth or treating a hyperproliferative disorder such
as cancer in a mammal (e.g., human) comprising administering to
said mammal a therapeutically effective amount of a compound of
Formula I, and/or solvates, hydrates and/or salts thereof, or a
composition thereof, in combination with a second chemotherapeutic
agent such as those described herein. For example, the present
invention includes a method of treating multiple myeloma, lymphoma,
acute myeloid leukemia, prostate cancer, breast cancer,
hepatocellular carcinoma, pancreatic cancer, and/or colorectal
cancer in a mammal (e.g., human), comprising administering to said
mammal a therapeutically effective amount of a compound of Formula
I, and/or solvates, hydrates and/or salts thereof, or a composition
thereof, in combination with a second chemotherapeutic agent such
as those described herein.
[0088] The present invention includes a method of treating lymphoma
in a mammal (e.g., human) comprising administering to said mammal a
therapeutically effective amount of a compound of Formula I, and/or
solvates, hydrates and/or salts thereof, or a composition thereof,
either alone or in combination with a second chemotherapeutic agent
such as an anti-B-cell antibody therapeutic (e.g., Rituxan and/or
Dacetuzumab), gemcitabine, corticosteroids (e.g., prednisolone
and/or dexamethasone), chemotherapy cocktails (e.g., CHOP
(cyclophosphamide, doxorubicin, vincristine, prednisolone) and/or
ICE (isfosfamide, cytoxan, etoposide)), a combination of biologics
and chemotherapy (e.g., Rituxan-10E, Dacetuzumab-Rituxan-ICE,
R-Gem, and/or D-R-Gem), an Akt inhibitor, a PI3K inhibitor (e.g,
GDC-0941 (Genentech) and/or GDC-0980 (Genentech)), rapamycin, a MEK
inhibitor (GDC-0973), a Bcl-2 inhibitor (ABT-263), and lymphoma
directed antibody drug conjugate (e.g., antiCD22 antibody drug
conjugate including but not limited to antiCD22-vcMMAE, and/or
antiCD79b-antibody drug conjugate including but not limited to
antiCD79b-vcMMAE).
[0089] The present invention includes a method of treating multiple
myeloma in a mammal (e.g., human) comprising administering to said
mammal a therapeutically effective amount of a compound of Formula
I, and/or solvates, hydrates and/or salts thereof, or a composition
thereof, either alone or in combination with a second
chemotherapeutic agent such as melphalan, thalidomide,
lenalidomide, pomolidamide, corticosteroids, dexamethasone,
prednisolone, and bortezomib or other proteasome inhibitor.
[0090] The present invention includes a method of treating multiple
myeloma, chronic lymphocytic leukemia (CLL), or acute myeloid
leukemia (AML) in a mammal (e.g., human) comprising administering
to said mammal a therapeutically effective amount of a compound of
Formula I, and/or solvates, hydrates and/or salts thereof, or a
composition thereof, either alone or in combination with a second
chemotherapeutic agent such as cytarabine (araC), anthracyclines
(e.g., daunorubicin and/or idarubicin), anti-myeloid antibody
therapeutics (e.g., SGN-33), anti-myeloid antibody-drug conjugates
(e.g., MYLOTARG.RTM.).
[0091] The present invention includes a method of treating chronic
lymphocytic leukemia (CLL) in a mammal (e.g., human) comprising
administering to said mammal a therapeutically effective amount of
a compound of Formula I, and/or solvates, hydrates and/or salts
thereof, or a composition thereof, either alone or in combination
with a second chemotherapeutic agent such as fludarabine,
cyclophosphamide, anti-B-cell antibody therapeutics (e.g., Rituxan
and/or Dacetuzumab).
[0092] The present invention includes a method of treating chronic
myeloid leukemia (CML) in a mammal (e.g., human) comprising
administering to said mammal a therapeutically effective amount of
a compound of Formula I, and/or solvates, hydrates and/or salts
thereof, or a composition thereof, either alone or in combination
with a second chemotherapeutic agent such as a BCR-abl inhibitor
(e.g., imatinib, nilotinib, and/or dasatinib). The present
invention includes a method of treating myelodysplastic diseases
(MDS) and myeloproliferative disorders including polycythemia vera
(PV), essential thrombocytosis (ET) or myclofibrosis (MF), in a
mammal (e.g., human) comprising administering to said mammal a
therapeutically effective amount of a compound of Formula I, and/or
solvates, hydrates and/or salts thereof, or a composition thereof,
either alone or in combination.
[0093] The present invention includes a method of using the present
compounds for in vitro, in situ, and in vivo diagnosis or treatment
of mammalian cells, organisms, or associated pathological
conditions.
[0094] Administration of the compounds of the present invention
(hereinafter the "active compound(s)") can be effected by any
method that enables delivery of the compounds to the site of
action. These methods include oral routes, intraduodenal routes,
parenteral injection (including intravenous, subcutaneous,
intramuscular, intravascular or infusion), topical, inhalation and
rectal administration.
[0095] The amount of the active compound administered will be
dependent on the subject being treated, the severity of the
disorder or condition, the rate of administration, the disposition
of the compound and the discretion of the prescribing physician.
However, an effective dosage is in the range of about 0.001 to
about 100 mg per kg body weight per day, preferably about 1 to
about 35 mg/kg/day, in single or divided doses. For a 70 kg human,
this would amount to about 0.05 to 7 g/day, preferably about 0.05
to about 2.5 g/day. In some instances, dosage levels below the
lower limit of the aforesaid range may be more than adequate, while
in other cases still larger doses may be employed without causing
any harmful side effect, provided that such larger doses are first
divided into several small doses for administration throughout the
day.
[0096] The active compound may be applied as a sole therapy or in
combination with one or more chemotherapeutic agents, for example
those described herein. Such conjoint treatment may be achieved by
way of the simultaneous, sequential or separate dosing of the
individual components of treatment.
[0097] The pharmaceutical composition may, for example, be in a
form suitable for oral administration as a tablet, capsule, pill,
powder, sustained release formulations, solution, suspension for
parenteral injection as a sterile solution, suspension or emulsion
for topical administration as an ointment or cream or for rectal
administration as a suppository. The pharmaceutical composition may
be in unit dosage forms suitable for single administration of
precise dosages. The pharmaceutical composition will include a
conventional pharmaceutical carrier or excipient and a compound
according to the invention as an active ingredient. In addition, it
may include other medicinal or pharmaceutical agents, carriers,
adjuvants, etc.
[0098] Exemplary parenteral administration forms include solutions
or suspensions of Formula I compounds in sterile aqueous solutions,
for example, aqueous propylene glycol or dextrose solutions. Such
dosage forms can be suitably buffered, if desired.
[0099] Suitable pharmaceutical carriers include inert diluents or
fillers, water and various organic solvents. The pharmaceutical
compositions may, if desired, contain additional ingredients such
as flavorings, binders, excipients and the like. Thus for oral
administration, tablets containing various excipients, such as
citric acid may be employed together with various disintegrants
such as starch, alginic acid and certain complex silicates and with
binding agents such as sucrose, gelatin and acacia. Additionally,
lubricating agents such as magnesium stearate, sodium lauryl
sulfate and talc are often useful for tabletting purposes. Solid
compositions of a similar type may also be employed in soft and
hard filled gelatin capsules. Preferred materials, therefore,
include lactose or milk sugar and high molecular weight
polyethylene glycols. When aqueous suspensions or elixirs are
desired for oral administration the active compound therein may be
combined with various sweetening or flavoring agents, coloring
matters or dyes and, if desired, emulsifying agents or suspending
agents, together with diluents such as water, ethanol, propylene
glycol, glycerin, or combinations thereof.
[0100] Methods of preparing various pharmaceutical compositions
with a specific amount of active compound are known, or will be
apparent, to those skilled in this art. For examples, see
Remington's Pharmaceutical Sciences, Mack Publishing Company,
Ester, Pa., 15.sup.th Edition (1975).
Administration of Formula I Compounds
[0101] The Formula I compounds of the invention may be administered
by any route appropriate to the condition to be treated. Suitable
routes include oral, parenteral (including subcutaneous,
intramuscular, intravenous, intraarterial, intradermal, intrathecal
and epidural), transdermal, rectal, nasal, topical (including
buccal and sublingual), vaginal, intraperitoneal, intrapulmonary
and intranasal. For local immunosuppressive treatment, the
compounds may be administered by intralesional administration,
including perfusing or otherwise contacting the graft with the
inhibitor before transplantation. It will be appreciated that the
preferred route may vary with for example the condition of the
recipient. Where the compound is administered orally, it may be
formulated as a pill, capsule, tablet, etc. with a pharmaceutically
acceptable carrier or excipient. Where the compound is administered
parenterally, it may be formulated with a pharmaceutically
acceptable parenteral vehicle and in a unit dosage injectable form,
as detailed below.
[0102] A dose to treat human patients may range from about 10 mg to
about 1000 mg of Formula I compound. A typical dose may be about
100 mg to about 300 mg of the compound. A dose may be administered
once a day (QID), twice per day (BID), or more frequently,
depending on the pharmacokinetic and pharmacodynamic properties,
including absorption, distribution, metabolism, and excretion of
the particular compound. In addition, toxicity factors may
influence the dosage and administration regimen. When administered
orally, the pill, capsule, or tablet may be ingested daily or less
frequently for a specified period of time. The regimen may be
repeated for a number of cycles of therapy.
Methods of Treatment with Formula I Compounds
[0103] Compounds of the present invention are useful for treating
hyperproliferative diseases, conditions and/or disorders including,
but not limited to, those characterized by over expression of Pim
kinases, e.g. Pim-1, Pim-2 and Pim-3 kinases. Accordingly, another
aspect of this invention includes methods of treating or preventing
diseases or conditions that can be treated or prevented by
inhibiting Pim kinase. In one embodiment, the method comprises
administering to a mammal in need thereof a therapeutically
effective amount of a compound of Formula I, or a stereoisomer,
geometric isomer, tautomer, or pharmaceutically acceptable salt
thereof. In one embodiment, a human patient is treated with a
compound of Formula I and a pharmaceutically acceptable carrier,
adjuvant, or vehicle, wherein said compound of Formula I is present
in an amount to detectably inhibit Pim kinase activity.
[0104] Cancers which can be treated according to the methods of
this invention include, but are not limited to, breast, ovary,
cervix, prostate, testis, genitourinary tract, esophagus, larynx,
glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung,
epidermoid carcinoma, large cell carcinoma, non-small cell lung
carcinoma (NSCLC), small cell carcinoma, lung adenocarcinoma, bone,
colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular
carcinoma, undifferentiated carcinoma, papillary carcinoma,
seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and
biliary passages, kidney carcinoma, myeloid disorders, lymphoid
disorders, hairy cells, buccal cavity and pharynx (oral), lip,
tongue, mouth, pharynx, small intestine, colon-rectum, large
intestine, rectum, brain and central nervous system, Hodgkin's and
leukemia.
[0105] Another aspect of this invention provides a compound of this
invention for use in the treatment of the diseases or conditions
described herein in a mammal, for example, a human, suffering from
such disease or condition. Also provided is the use of a compound
of this invention in the preparation of a medicament for the
treatment of the diseases and conditions described herein in a
warm-blooded animal, such as a mammal, for example a human,
suffering from such disorder.
Pharmaceutical Formulations
[0106] In order to use a Formula I compound for the therapeutic
treatment (including prophylactic treatment) of mammals including
humans, it is normally formulated in accordance with standard
pharmaceutical practice as a pharmaceutical composition. According
to this aspect of the invention there is provided a pharmaceutical
composition comprising a compound of this invention in association
with a pharmaceutically acceptable diluent or carrier.
[0107] A typical formulation is prepared by mixing a Formula I
compound and a carrier, diluent or excipient. Suitable carriers,
diluents and excipients are well known to those skilled in the art
and include materials such as carbohydrates, waxes, water soluble
and/or swellable polymers, hydrophilic or hydrophobic materials,
gelatin, oils, solvents, water and the like. The particular
carrier, diluent or excipient used will depend upon the means and
purpose for which the compound of the present invention is being
applied. Solvents are generally selected based on solvents
recognized by persons skilled in the art as safe (GRAS) to be
administered to a mammal. In general, safe solvents are non-toxic
aqueous solvents such as water and other non-toxic solvents that
are soluble or miscible in water. Suitable aqueous solvents include
water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG
400, PEG 300), etc. and mixtures thereof. The formulations may also
include one or more buffers, stabilizing agents, surfactants,
wetting agents, lubricating agents, emulsifiers, suspending agents,
preservatives, antioxidants, opaquing agents, glidants, processing
aids, colorants, sweeteners, perfuming agents, flavoring agents and
other known additives to provide an elegant presentation of the
drug (i.e., a compound of the present invention or pharmaceutical
composition thereof) or aid in the manufacturing of the
pharmaceutical product (i.e., medicament).
[0108] The formulations may be prepared using conventional
dissolution and mixing procedures. For example, the bulk drug
substance (i.e., compound of the present invention or stabilized
form of the Formula I compound (e.g., complex with a cyclodextrin
derivative or other known complexation agent) is dissolved in a
suitable solvent in the presence of one or more of the excipients
described above. The compound of the present invention is typically
formulated into pharmaceutical dosage forms to provide an easily
controllable dosage of the drug and to enable patient compliance
with the prescribed regimen.
[0109] The pharmaceutical composition (or formulation) for
application may be packaged in a variety of ways depending upon the
method used for administering the drug. Generally, an article for
distribution includes a container having deposited therein the
pharmaceutical formulation in an appropriate form. Suitable
containers are well known to those skilled in the art and include
materials such as bottles (plastic and glass), sachets, ampoules,
plastic bags, metal cylinders, and the like. The container may also
include a tamper-proof assemblage to prevent indiscreet access to
the contents of the package. In addition, the container has
deposited thereon a label that describes the contents of the
container. The label may also include appropriate warnings.
[0110] Pharmaceutical formulations of the compounds of the present
invention may be prepared for various routes and types of
administration. For example, a compound of Formula I having the
desired degree of purity may optionally be mixed with
pharmaceutically acceptable diluents, carriers, excipients or
stabilizers (Remington's Pharmaceutical Sciences (1980) 16.sup.th
edition, Osol, A. Ed.), in the form of a lyophilized formulation,
milled powder, or an aqueous solution. Formulation may be conducted
by mixing at ambient temperature at the appropriate pH, and at the
desired degree of purity, with physiologically acceptable carriers,
i.e., carriers that are non-toxic to recipients at the dosages and
concentrations employed. The pH of the formulation depends mainly
on the particular use and the concentration of compound, but may
range from about 3 to about 8. Formulation in an acetate buffer at
pH 5 is a suitable embodiment.
[0111] The compound of this invention for use herein is preferably
sterile. In particular, formulations to be used for in vivo
administration must be sterile. Such sterilization is readily
accomplished by filtration through sterile filtration
membranes.
[0112] The compound ordinarily can be stored as a solid
composition, a lyophilized formulation or as an aqueous
solution.
[0113] The pharmaceutical compositions of the invention comprising
a Formula I compound will be formulated, dosed and administered in
a fashion, i.e., amounts, concentrations, schedules, course,
vehicles and route of administration, consistent with good medical
practice. Factors for consideration in this context include the
particular disorder being treated, the particular mammal being
treated, the clinical condition of the individual patient, the
cause of the disorder, the site of delivery of the agent, the
method of administration, the scheduling of administration, and
other factors known to medical practitioners. The "therapeutically
effective amount" of the compound to be administered will be
governed by such considerations, and is the minimum amount
necessary to prevent, ameliorate, or treat the coagulation factor
mediated disorder. Such amount is preferably below the amount that
is toxic to the host or renders the host significantly more
susceptible to bleeding.
[0114] As a general proposition, the initial pharmaceutically
effective amount of the Formula I compound administered
parenterally per dose will be in the range of about 0.01-100 mg/kg,
namely about 0.1 to 20 mg/kg of patient body weight per day, with
the typical initial range of compound used being 0.3 to 15
mg/kg/day.
[0115] Acceptable diluents, carriers, excipients and stabilizers
are nontoxic to recipients at the dosages and concentrations
employed, and include buffers such as phosphate, citrate and other
organic acids; antioxidants including ascorbic acid and methionine;
preservatives (such as octadecyldimethylbenzyl ammonium chloride;
hexamethonium chloride; benzalkonium chloride, benzethonium
chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as
methyl or propyl paraben; catechol; resorcinol; cyclohexanol;
3-pentanol; and m-cresol); low molecular weight (less than about 10
residues) polypeptides; proteins, such as serum albumin, gelatin,
or immunoglobulins; hydrophilic polymers such as
polyvinylpyrrolidone; amino acids such as glycine, glutamine,
asparaginic, histidine, arginine, or lysine; monosaccharides,
disaccharides and other carbohydrates including glucose, mannose,
or dextrins; chelating agents such as EDTA; sugars such as sucrose,
mannitol, trehalose or sorbitol; salt-forming counter-ions such as
sodium; metal complexes (e.g., Zn-protein complexes); and/or
non-ionic surfactants such as TWEEN.TM., PLURONICS.TM. or
polyethylene glycol (PEG). The active pharmaceutical ingredients
may also be entrapped in microcapsules prepared, for example, by
coacervation techniques or by interfacial polymerization, for
example, hydroxymethylcellulose or gelatin-microcapsules and
poly-(methylmethacylate) microcapsules, respectively, in colloidal
drug delivery systems (for example, liposomes, albumin
microspheres, microemulsions, nano-particles and nanocapsules) or
in macroemulsions. Such techniques are disclosed in Remington's
Pharmaceutical Sciences 16.sup.th edition, Osol, A. Ed. (1980).
[0116] Sustained-release preparations of Formula I compounds may be
prepared. Suitable examples of sustained-release preparations
include semipermeable matrices of solid hydrophobic polymers
containing a compound of Formula I, which matrices are in the form
of shaped articles, e.g., films, or microcapsules. Examples of
sustained-release matrices include polyesters, hydrogels (for
example, poly(2-hydroxyethyl-methacrylate), or poly(vinyl
alcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of
L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable
ethylene-vinyl acetate, degradable lactic acid-glycolic acid
copolymers such as the LUPRON DEPOT.TM. (injectable microspheres
composed of lactic acid-glycolic acid copolymer and leuprolide
acetate) and poly-D-(-)-3-hydroxybutyric acid. The formulations
include those suitable for the administration routes detailed
herein.
[0117] The formulations may conveniently be presented in unit
dosage form and may be prepared by any of the methods well known in
the art of pharmacy. Techniques and formulations generally are
found in Remington's Pharmaceutical Sciences (Mack Publishing Co.,
Easton, Pa.). Such methods include the step of bringing into
association the active ingredient with the carrier which
constitutes one or more accessory ingredients. In general the
formulations are prepared by uniformly and intimately bringing into
association the active ingredient with liquid carriers or finely
divided solid carriers or both, and then, if necessary, shaping the
product.
[0118] Formulations of a compound of Formula I suitable for oral
administration may be prepared as discrete units such as pills,
capsules, cachets or tablets each containing a predetermined amount
of a compound of Formula I.
[0119] Compressed tablets may be prepared by compressing in a
suitable machine the active ingredient in a free-flowing form such
as a powder or granules, optionally mixed with a binder, lubricant,
inert diluent, preservative, surface active or dispersing agent.
Molded tablets may be made by molding in a suitable machine a
mixture of the powdered active ingredient moistened with an inert
liquid diluent. The tablets may optionally be coated or scored and
optionally are formulated so as to provide slow or controlled
release of the active ingredient therefrom.
[0120] Tablets, troches, lozenges, aqueous or oil suspensions,
dispersible powders or granules, emulsions, hard or soft capsules,
e.g., gelatin capsules, syrups or elixirs may be prepared for oral
use. Formulations of compounds of Formula I intended for oral use
may be prepared according to any method known to the art for the
manufacture of pharmaceutical compositions and such compositions
may contain one or more agents including sweetening agents,
flavoring agents, coloring agents and preserving agents, in order
to provide a palatable preparation. Tablets containing the active
ingredient in admixture with non-toxic pharmaceutically acceptable
excipient which are suitable for manufacture of tablets are
acceptable. These excipients may be, for example, inert diluents,
such as calcium or sodium carbonate, lactose, calcium or sodium
phosphate; granulating and disintegrating agents, such as maize
starch, or alginic acid; binding agents, such as starch, gelatin or
acacia; and lubricating agents, such as magnesium stearate, stearic
acid or talc. Tablets may be uncoated or may be coated by known
techniques including microencapsulation to delay disintegration and
adsorption in the gastrointestinal tract and thereby provide a
sustained action over a longer period. For example, a time delay
material such as glyceryl monostearate or glyceryl distearate alone
or with a wax may be employed.
[0121] For treatment of the eye or other external tissues, e.g.,
mouth and skin, the formulations are preferably applied as a
topical ointment or cream containing the active ingredient(s) in an
amount of for example, 0.075 to 20% w/w. When formulated in an
ointment, the active ingredients may be employed with either a
paraffinic or a water-miscible ointment base. Alternatively, the
active ingredients may be formulated in a cream with an
oil-in-water cream base.
[0122] If desired, the aqueous phase of the cream base may include
a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl
groups such as propylene glycol, butane 1,3-diol, mannitol,
sorbitol, glycerol and polyethylene glycol (including PEG 400) and
mixtures thereof. The topical formulations may desirably include a
compound which enhances absorption or penetration of the active
ingredient through the skin or other affected areas. Examples of
such dermal penetration enhancers include dimethyl sulfoxide and
related analogs.
[0123] The oily phase of the emulsions of this invention may be
constituted from known ingredients in a known manner. While the
phase may comprise merely an emulsifier, it desirably comprises a
mixture of at least one emulsifier with a fat or oil, or with both
a fat and an oil. Preferably, a hydrophilic emulsifier is included
together with a lipophilic emulsifier which acts as a stabilizer.
It is also preferred to include both an oil and a fat. Together,
the emulsifier(s) with or without stabilizer(s) make up the
so-called emulsifying wax, and the wax together with the oil and
fat make up the so-called emulsifying ointment base which forms the
oily dispersed phase of the cream formulations. Emulsifiers and
emulsion stabilizers suitable for use in the formulation of the
invention include Tween.RTM. 60, Span.RTM. 80, cetostearyl alcohol,
benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium
lauryl sulfate.
[0124] Aqueous suspensions of Formula I compounds contain the
active materials in admixture with excipients suitable for the
manufacture of aqueous suspensions. Such excipients include a
suspending agent, such as sodium carboxymethylcellulose,
croscarmellose, povidone, methylcellulose, hydroxypropyl
methylcellulose, sodium alginate, polyvinylpyrrolidone, gum
tragacanth and gum acacia, and dispersing or wetting agents such as
a naturally occurring phosphatide (e.g., lecithin), a condensation
product of an alkylene oxide with a fatty acid (e.g.,
polyoxyethylene stearate), a condensation product of ethylene oxide
with a long chain aliphatic alcohol (e.g.,
heptadecaethyleneoxycetanol), a condensation product of ethylene
oxide with a partial ester derived from a fatty acid and a hexitol
anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous
suspension may also contain one or more preservatives such as ethyl
or n-propyl p-hydroxybenzoate, one or more coloring agents, one or
more flavoring agents and one or more sweetening agents, such as
sucrose or saccharin.
[0125] The pharmaceutical compositions of compounds of Formula I
may be in the form of a sterile injectable preparation, such as a
sterile injectable aqueous or oleaginous suspension. This
suspension may be formulated according to the known art using those
suitable dispersing or wetting agents and suspending agents which
have been mentioned above. The sterile injectable preparation may
also be a sterile injectable solution or suspension in a non-toxic
parenterally acceptable diluent or solvent, such as a solution in
1,3-butanediol or prepared as a lyophilized powder. Among the
acceptable vehicles and solvents that may be employed are water,
Ringer's solution and isotonic sodium chloride solution. In
addition, sterile fixed oils may conventionally be employed as a
solvent or suspending medium. For this purpose any bland fixed oil
may be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid may likewise be used in
the preparation of injectables.
[0126] The amount of active ingredient that may be combined with
the carrier material to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration. For example, a time-release formulation intended
for oral administration to humans may contain approximately 1 to
1000 mg of active material compounded with an appropriate and
convenient amount of carrier material which may vary from about 5
to about 95% of the total compositions (weight:weight). The
pharmaceutical composition can be prepared to provide easily
measurable amounts for administration. For example, an aqueous
solution intended for intravenous infusion may contain from about 3
to 500 .mu.g of the active ingredient per milliliter of solution in
order that infusion of a suitable volume at a rate of about 30
mL/hr can occur.
[0127] Formulations suitable for parenteral administration include
aqueous and non-aqueous sterile injection solutions which may
contain anti-oxidants, buffers, bacteriostats and solutes which
render the formulation isotonic with the blood of the intended
recipient; and aqueous and non-aqueous sterile suspensions which
may include suspending agents and thickening agents.
[0128] Formulations suitable for topical administration to the eye
also include eye drops wherein the active ingredient is dissolved
or suspended in a suitable carrier, especially an aqueous solvent
for the active ingredient. The active ingredient is preferably
present in such formulations in a concentration of about 0.5 to 20%
w/w, for example about 0.5 to 10% w/w, for example about 1.5%
w/w.
[0129] Formulations suitable for topical administration in the
mouth include lozenges comprising the active ingredient in a
flavored basis, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert basis such as gelatin
and glycerin, or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier.
[0130] Formulations for rectal administration may be presented as a
suppository with a suitable base comprising for example cocoa
butter or a salicylate.
[0131] Formulations suitable for intrapulmonary or nasal
administration have a particle size for example in the range of 0.1
to 500 microns (including particle sizes in a range between 0.1 and
500 microns in increments microns such as 0.5, 1, 30 microns, 35
microns, etc.), which is administered by rapid inhalation through
the nasal passage or by inhalation through the mouth so as to reach
the alveolar sacs. Suitable formulations include aqueous or oily
solutions of the active ingredient. Formulations suitable for
aerosol or dry powder administration may be prepared according to
conventional methods and may be delivered with other therapeutic
agents such as compounds heretofore used in the treatment or
prophylaxis disorders as described below.
[0132] Formulations suitable for vaginal administration may be
presented as pessaries, tampons, creams, gels, pastes, foams or
spray formulations containing in addition to the active ingredient
such carriers as are known in the art to be appropriate.
[0133] The formulations may be packaged in unit-dose or multi-dose
containers, for example sealed ampoules and vials, and may be
stored in a freeze-dried (lyophilized) condition requiring only the
addition of the sterile liquid carrier, for example water, for
injection immediately prior to use. Extemporaneous injection
solutions and suspensions are prepared from sterile powders,
granules and tablets of the kind previously described. Preferred
unit dosage formulations are those containing a daily dose or unit
daily sub-dose, as herein above recited, or an appropriate fraction
thereof, of the active ingredient.
[0134] The invention further provides veterinary compositions
comprising at least one active ingredient as above defined together
with a veterinary carrier therefore. Veterinary carriers are
materials useful for the purpose of administering the composition
and may be solid, liquid or gaseous materials which are otherwise
inert or acceptable in the veterinary art and are compatible with
the active ingredient. These veterinary compositions may be
administered parenterally, orally or by any other desired
route.
Combination Therapy
[0135] The compounds of Formula I may be employed alone or in
combination with other therapeutic agents for the treatment of a
disease or disorder described herein, such as a hyperproliferative
disorder (e.g., cancer). In certain embodiments, a compound of
Formula I is combined in a pharmaceutical combination formulation,
or dosing regimen as combination therapy, with a second compound
that has anti-hyperproliferative properties or that is useful for
treating a hyperproliferative disorder (e.g., cancer). The second
compound of the pharmaceutical combination formulation or dosing
regimen preferably has complementary activities to the compound of
Formula I such that they do not adversely affect each other. Such
compounds are suitably present in combination in amounts that are
effective for the purpose intended. In one embodiment, a
composition of this invention comprises a compound of Formula I, in
combination with a chemotherapeutic agent such as described
herein.
[0136] The combination therapy may be administered as a
simultaneous or sequential regimen. When administered sequentially,
the combination may be administered in two or more administrations.
The combined administration includes coadministration, using
separate formulations or a single pharmaceutical formulation, and
consecutive administration in either order, wherein preferably
there is a time period while both (or all) active agents
simultaneously exert their biological activities.
[0137] Suitable dosages for any of the above coadministered agents
are those presently used and may be lowered due to the combined
action (synergy) of the newly identified agent and other
chemotherapeutic agents or treatments.
[0138] The combination therapy may provide "synergy" and prove
"synergistic", i.e., the effect achieved when the active
ingredients used together is greater than the sum of the effects
that results from using the compounds separately. A synergistic
effect may be attained when the active ingredients are: (1)
co-formulated and administered or delivered simultaneously in a
combined, unit dosage formulation; (2) delivered by alternation or
in parallel as separate formulations; or (3) by some other regimen.
When delivered in alternation therapy, a synergistic effect may be
attained when the compounds are administered or delivered
sequentially, e.g., by different injections in separate syringes,
separate pills or capsules, or separate infusions. In general,
during alternation therapy, an effective dosage of each active
ingredient is administered sequentially, i.e., serially, whereas in
combination therapy, effective dosages of two or more active
ingredients are administered together.
[0139] In a particular embodiment of anti-cancer therapy, a
compound of Formula I, or a stereoisomer, geometric isomer,
tautomer, solvate, metabolite, or pharmaceutically acceptable salt
or prodrug thereof, may be combined with other chemotherapeutic,
hormonal or antibody agents such as those described herein, as well
as combined with surgical therapy and radiotherapy. Combination
therapies according to the present invention thus comprise the
administration of at least one compound of Formula I, or a
stereoisomer, geometric isomer, tautomer, solvate, metabolite, or
pharmaceutically acceptable salt or prodrug thereof, and the use of
at least one other cancer treatment method. The amounts of the
compound(s) of Formula I and the other pharmaceutically active
chemotherapeutic agent(s) and the relative timings of
administration will be selected in order to achieve the desired
combined therapeutic effect.
Metabolites of Formula I Compounds
[0140] Also falling within the scope of this invention are the in
vivo metabolic products of Formula I described herein. Such
products may result for example from the oxidation, reduction,
hydrolysis, amidation, deamidation, esterification,
deesterification, enzymatic cleavage, and the like, of the
administered compound. Accordingly, the invention includes
metabolites of compounds of Formula I, including compounds produced
by a process comprising contacting a compound of this invention
with a mammal for a period of time sufficient to yield a metabolic
product thereof.
[0141] Metabolite products typically are identified by preparing a
radiolabelled (e.g., .sup.14C or .sup.3H) isotope of a compound of
the invention, administering it parenterally in a detectable dose
(e.g., greater than about 0.5 mg/kg) to an animal such as rat,
mouse, guinea pig, monkey, or to man, allowing sufficient time for
metabolism to occur (typically about 30 seconds to 30 hours) and
isolating its conversion products from the urine, blood or other
biological samples. These products are easily isolated since they
are labeled (others are isolated by the use of antibodies capable
of binding epitopes surviving in the metabolite). The metabolite
structures are determined in conventional fashion, e.g., by MS,
LC/MS or NMR analysis. In general, analysis of metabolites is done
in the same way as conventional drug metabolism studies well known
to those skilled in the art. The metabolite products, so long as
they are not otherwise found in vivo, may be useful in diagnostic
assays for therapeutic dosing of the compounds of the
invention.
Articles of Manufacture
[0142] In another embodiment of the invention, an article of
manufacture, or "kit", containing materials useful for the
treatment of the diseases and disorders described above is
provided. The kit comprises a container comprising a compound of
Formula I. The kit may further comprise a label or package insert,
on or associated with the container. The term "package insert" is
used to refer to instructions customarily included in commercial
packages of therapeutic products, that contain information about
the indications, usage, dosage, administration, contraindications
and/or warnings concerning the use of such therapeutic products.
Suitable containers include, for example, bottles, vials, syringes,
blister pack, etc. The container may be formed from a variety of
materials such as glass or plastic. The container may hold a
compound of Formula I or II or a formulation thereof which is
effective for treating the condition and may have a sterile access
port (for example, the container may be an intravenous solution bag
or a vial having a stopper pierceable by a hypodermic injection
needle). At least one active agent in the composition is a compound
of Formula I. The label or package insert indicates that the
composition is used for treating the condition of choice, such as
cancer. In addition, the label or package insert may indicate that
the patient to be treated is one having a disorder such as a
hyperproliferative disorder, neurodegeneration, cardiac
hypertrophy, pain, migraine or a neurotraumatic disease or event.
In one embodiment, the label or package inserts indicates that the
composition comprising a compound of Formula I can be used to treat
a disorder resulting from abnormal cell growth. The label or
package insert may also indicate that the composition can be used
to treat other disorders. Alternatively, or additionally, the
article of manufacture may further comprise a second container
comprising a pharmaceutically acceptable buffer, such as
bacteriostatic water for injection (BWFI), phosphate-buffered
saline, Ringer's solution and dextrose solution. It may further
include other materials desirable from a commercial and user
standpoint, including other buffers, diluents, filters, needles,
and syringes.
[0143] The kit may further comprise directions for the
administration of the compound of Formula I and, if present, the
second pharmaceutical formulation. For example, if the kit
comprises a first composition comprising a compound of Formula I,
and a second pharmaceutical formulation, the kit may further
comprise directions for the simultaneous, sequential or separate
administration of the first and second pharmaceutical compositions
to a patient in need thereof.
[0144] In another embodiment, the kits are suitable for the
delivery of solid oral forms of a compound of Formula I, such as
tablets or capsules. Such a kit preferably includes a number of
unit dosages. Such kits can include a card having the dosages
oriented in the order of their intended use. An example of such a
kit is a "blister pack". Blister packs are well known in the
packaging industry and are widely used for packaging pharmaceutical
unit dosage forms. If desired, a memory aid can be provided, for
example in the form of numbers, letters, or other markings or with
a calendar insert, designating the days in the treatment schedule
in which the dosages can be administered.
[0145] According to one embodiment, a kit may comprise (a) a first
container with a compound of Formula I contained therein; and
optionally (b) a second container with a second pharmaceutical
formulation contained therein, wherein the second pharmaceutical
formulation comprises a second compound with
anti-hyperproliferative activity. Alternatively, or additionally,
the kit may further comprise a third container comprising a
pharmaceutically-acceptable buffer, such as bacteriostatic water
for injection (BWFI), phosphate-buffered saline, Ringer's solution
and dextrose solution. It may further include other materials
desirable from a commercial and user standpoint, including other
buffers, diluents, filters, needles, and syringes.
[0146] In certain other embodiments wherein the kit comprises a
composition of Formula I and a second therapeutic agent, the kit
may comprise a container for containing the separate compositions
such as a divided bottle or a divided foil packet, however, the
separate compositions may also be contained within a single,
undivided container. Typically, the kit comprises directions for
the administration of the separate components. The kit form is
particularly advantageous when the separate components are
preferably administered in different dosage forms (e.g., oral and
parenteral), are administered at different dosage intervals, or
when titration of the individual components of the combination is
desired by the prescribing physician.
Preparation of Formula I Compounds
[0147] Compounds of Formula I may be synthesized by synthetic
routes that include processes analogous to those well-known in the
chemical arts, particularly in light of the description contained
herein, and those for other heterocycles described in:
Comprehensive Heterocyclic Chemistry II, Editors Katritzky and
Rees, Elsevier, 1997, e.g. Volume 3; Liebigs Annalen der Chemie,
(9):1910-16, (1985); Helvetica Chimica Acta, 41:1052-60, (1958);
Arzneimittel-Forschung, 40(12):1328-31, (1990), each of which are
expressly incorporated by reference. Starting materials are
generally available from commercial sources such as Aldrich
Chemicals (Milwaukee, Wis.) or are readily prepared using methods
well known to those skilled in the art (e.g., prepared by methods
generally described in Louis F. Fieser and Mary Fieser, Reagents
for Organic Synthesis, v. 1-23, Wiley, N.Y. (1967-2006 ed.), or
Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed.
Springer-Verlag, Berlin, including supplements (also available via
the Beilstein online database).
[0148] Synthetic chemistry transformations and protecting group
methodologies (protection and deprotection) useful in synthesizing
Formula I compounds and necessary reagents and intermediates are
known in the art and include, for example, those described in R.
Larock, Comprehensive Organic Transformations, VCH Publishers
(1989); T. W. Greene and P. G. M. Wuts, Protective Groups in
Organic Synthesis, 3.sup.rd Ed., John Wiley and Sons (1999); and L.
Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John
Wiley and Sons (1995) and subsequent editions thereof.
[0149] Compounds of Formula I may be prepared singly or as compound
libraries comprising at least 2, for example 5 to 1,000 compounds,
or 10 to 100 compounds. Libraries of compounds of Formula I may be
prepared by a combinatorial `split and mix` approach or by multiple
parallel syntheses using either solution phase or solid phase
chemistry, by procedures known to those skilled in the art. Thus
according to a further aspect of the invention there is provided a
compound library comprising at least 2 compounds, or
pharmaceutically acceptable salts thereof.
[0150] The General Procedures and Examples provide exemplary
methods for preparing Formula I compounds. Those skilled in the art
will appreciate that other synthetic routes may be used to
synthesize the Formula I compounds. Although specific starting
materials and reagents are depicted and discussed in the Figures,
General Procedures, and Examples, other starting materials and
reagents can be easily substituted to provide a variety of
derivatives and/or reaction conditions. In addition, many of the
exemplary compounds prepared by the described methods can be
further modified in light of this disclosure using conventional
chemistry well known to those skilled in the art.
[0151] In preparing compounds of Formulas I, protection of remote
functionality (e.g., primary or secondary amine) of intermediates
may be necessary. The need for such protection will vary depending
on the nature of the remote functionality and the conditions of the
preparation methods. Suitable amino-protecting groups include
acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl
(CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc). The need for such
protection is readily determined by one skilled in the art. For a
general description of protecting groups and their use, see T. W.
Greene, Protective Groups in Organic Synthesis, John Wiley &
Sons, New York, 1991.
Methods of Separation
[0152] In the methods of preparing Formula I compounds, it may be
advantageous to separate reaction products from one another and/or
from starting materials. The desired products of each step or
series of steps is separated and/or purified to the desired degree
of homogeneity by the techniques common in the art. Typically such
separations involve multiphase extraction, crystallization from a
solvent or solvent mixture, distillation, sublimation, or
chromatography. Chromatography can involve any number of methods
including, for example: reverse-phase and normal phase; size
exclusion; ion exchange; high, medium and low pressure liquid
chromatography methods and apparatus; small scale analytical;
simulated moving bed (SMB) and preparative thin or thick layer
chromatography, as well as techniques of small scale thin layer and
flash chromatography.
[0153] Another class of separation methods involves treatment of a
mixture with a reagent selected to bind to or render otherwise
separable a desired product, unreacted starting material, reaction
by product, or the like. Such reagents include adsorbents or
absorbents such as activated carbon, molecular sieves, ion exchange
media, or the like. Alternatively, the reagents can be acids in the
case of a basic material, bases in the case of an acidic material,
binding reagents such as antibodies, binding proteins, selective
chelators such as crown ethers, liquid/liquid ion extraction
reagents (LIX), or the like. Selection of appropriate methods of
separation depends on the nature of the materials involved, such
as, boiling point and molecular weight in distillation and
sublimation, presence or absence of polar functional groups in
chromatography, stability of materials in acidic and basic media in
multiphase extraction, and the like.
[0154] Diastereomeric mixtures can be separated into their
individual diastereomers on the basis of their physical chemical
differences by methods well known to those skilled in the art, such
as by chromatography and/or fractional crystallization. Enantiomers
can be separated by converting the enantiomeric mixture into a
diastereomeric mixture by reaction with an appropriate optically
active compound (e.g., chiral auxiliary such as a chiral alcohol or
Mosher's acid chloride), separating the diastereomers and
converting (e.g., hydrolyzing) the individual diastereoisomers to
the corresponding pure enantiomers. Also, some of the compounds of
the present invention may be atropisomers (e.g., substituted
biaryls) and are considered as part of this invention. Enantiomers
can also be separated by use of a chiral HPLC column.
[0155] A single stereoisomer, e.g., an enantiomer, substantially
free of its stereoisomer may be obtained by resolution of the
racemic mixture using a method such as formation of diastereomers
using optically active resolving agents (Eliel, E. and Wilen, S.
"Stereochemistry of Organic Compounds," John Wiley & Sons,
Inc., New York, 1994; Lochmuller, C. H., (1975) J. Chromatogr.,
113(3):283-302). Racemic mixtures of chiral compounds of the
invention can be separated and isolated by any suitable method,
including: (1) formation of ionic, diastereomeric salts with chiral
compounds and separation by fractional crystallization or other
methods, (2) formation of diastereomeric compounds with chiral
derivatizing reagents, separation of the diastereomers, and
conversion to the pure stereoisomers, and (3) separation of the
substantially pure or enriched stereoisomers directly under chiral
conditions. See: "Drug Stereochemistry, Analytical Methods and
Pharmacology," Irving W. Wainer, Ed., Marcel Dekker, Inc., New York
(1993).
[0156] Under method (1), diastereomeric salts can be formed by
reaction of enantiomerically pure chiral bases such as brucine,
quinine, ephedrine, strychnine,
.alpha.-methyl-.beta.-phenylethylamine (amphetamine), and the like
with asymmetric compounds bearing acidic functionality, such as
carboxylic acid and sulfonic acid. The diastereomeric salts may be
induced to separate by fractional crystallization or ionic
chromatography. For separation of the optical isomers of amino
compounds, addition of chiral carboxylic or sulfonic acids, such as
camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid
can result in formation of the diastereomeric salts.
[0157] Alternatively, by method (2), the substrate to be resolved
is reacted with one enantiomer of a chiral compound to form a
diastereomeric pair (E. and Wilen, S. "Stereochemistry of Organic
Compounds", John Wiley & Sons, Inc., 1994, p. 322).
Diastereomeric compounds can be formed by reacting asymmetric
compounds with enantiomerically pure chiral derivatizing reagents,
such as menthyl derivatives, followed by separation of the
diastereomers and hydrolysis to yield the pure or enriched
enantiomer. A method of determining optical purity involves making
chiral esters, such as a menthyl ester, e.g., (-) menthyl
chloroformate in the presence of base, or Mosher ester,
.alpha.-methoxy-.alpha.-(trifluoromethyl)phenyl acetate of the
racemic mixture and analyzing the .sup.1H NMR spectrum for the
presence of the two atropisomeric enantiomers or diastereomers
(Jacob III. J. Org. Chem. (1982) 47:4165). Stable diastereomers of
atropisomeric compounds can be separated and isolated by normal-
and reverse-phase chromatography following methods for separation
of atropisomeric naphthyl-isoquinolines (WO 96/15111). By method
(3), a racemic mixture of two enantiomers can be separated by
chromatography using a chiral stationary phase ("Chiral Liquid
Chromatography" (1989) W. J. Lough, Ed., Chapman and Hall, New
York; Okamoto, J. Chromatogr., (1990) 513:375-378). Enriched or
purified enantiomers can be distinguished by methods used to
distinguish other chiral molecules with asymmetric carbon atoms,
such as optical rotation and circular dichroism.
General Preparative Procedures
[0158] Scheme 1 shows a general synthesis of compounds 13.
4-R.sup.1 Substituted 6-azaindazole 5 may be made through a 3-step
synthesis starting from 2-bromo-4-methyl-5-nitropyridine 1.
Installment of R.sup.1 group by Suzuki reaction, followed by nitro
group reduction and oxidative indazole ring formation furnishes
compound 5. Subsequent iodination and SEM protection may provide a
mixture of regioisomers 7a and 8a. Other suitable protection groups
such as tetrahydropyran, Boc groups, etc, may be alternatives to
SEM groups. The addition of R.sup.2 group may be accomplished
either through direct Suzuki, Buchwald or Goldberg reaction or
starting from tin reagents 7b and 8b through Stine reaction.
Further modification of R.sup.2 group may be rendered by either
direct SnAr or Buchwald reaction. Compounds 13 may be made from a
mixture of 11 and 12 by using acidic, basic or fluorinated reagents
in a suitable solvent.
##STR00436## ##STR00437##
[0159] Scheme 2 describes a general synthesis of compounds 20.
5-Bromo-6-azaindazole 15 may be made from
2-bromo-4-methyl-5-aminopyridine 14 by an oxidative cyclization,
described in J. Chem. Soc., Perkin Trans. 1, (1980), 2398-2404 and
Bioorganic & Medicinal Chemistry (2007), 15/6:2441-2452.
Compound 17 may be made by iodination of compound 15, followed by
tetrahydropyran protection. Compound 18 may be synthesized from
compound 17 either by Suzuki, Stille or Buchwald reaction
regioselectively. Compound 19 may be made from compound 18 through
direct SnAr, Suzuki or Buchwald reaction. Compound 20 may be made
from compound 19 through acid mediated removal of tetrahydropyran
protecting group. Other alternative protecting groups, e.g. SEM,
Boc, etc, may be used instead of tetrahydropyran.
##STR00438##
EXAMPLES
Intermediates
Example 1
4-methyl-5-nitro-2,3'-bipyridine
##STR00439##
[0161] To a solution of 2-bromo-4-methyl-5-nitropyridine (217 g, 1
mol) in DMF (2000 mL) was added Pd(dppf) Cl.sub.2 (5 g), saturated
solution of Na.sub.2CO.sub.3 (200 mL) and pyridin-3-ylboronic acid
(147 g, 1.2 mol). The mixture was stirred under argon for 6 h at
100. After cooling down, the solvent was removed under reduced
pressure evaporation and the residue was purified by silica-gel
column chromatography (mobile phase: EA:PE=1:1) to afford
4-methyl-5-nitro-2,3'-bipyridine (172 g, 80%).
Example 2
4-methyl-2,3'-bipyridin-5-amine
##STR00440##
[0163] A mixture of 4-methyl-5-nitro-2,3'-bipyridine (215 g, 1
mol), Pd/C (10 g, 10%) and MeOH (1000 mL) was stirred at room
temperature for 16 h under 10 atm of hydrogen. After reaction, the
mixture was filtered. The filtrate was evaporated at reduced
pressure to afford 4-methyl-2,3'-bipyridin-5-amine as a yellow
solid (152 g, 82%)
Example 3
5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine
##STR00441##
[0165] To a solution of 4-methyl-2,3'-bipyridin-5-amine (185 g, 1
mol) in AcOH (27 L) was added aq. NaNO.sub.2 solution (82 g, 1.2
mol, 100 mL). The mixture was stirred for 16 h at room temperature.
After reaction, the solvent was removed and the residue was
purified by silica-gel column chromatography (mobile phase:
EA:PE=1:1) to give 5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine as a
yellow solid (98 g, 50%)
Example 4
3-iodo-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine
##STR00442##
[0167] 5-(Pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine (196 g, 1 mol)
was dissolved in 1000 mL DMF. KOH (112 g, 2 mol) was added. After
stirring for 30 min, I.sub.2 (303 g, 1.2 mol) was added. The
mixture was stirred for 1 h at room temperature. After reaction,
the reaction was quenched with saturated aq. Na.sub.2S.sub.2O.sub.5
solution followed by the addition water (5 L). The solid was
filtered and washed with water to give
3-iodo-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine as a yellow
solid (290 g, 90%)
Example 5
3-iodo-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3-
,4-c]pyridine and
3-iodo-5-(pyridin-3-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo
[3,4-c]pyridine
##STR00443##
[0169] To a solution of
3-iodo-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine (100 g, 0.31
mol) in CH.sub.2Cl.sub.2 (500 mL) was added DIPEA (120 g, 0.93 mol)
and SEM-C1 (77 g, 0.46 mol). The mixture was stirred at room
temperature for 1 hr. After removing the solvent, the residue was
purified by silica-gel column chromatography (mobile phase:
EA:PE=1:1) to afford a mixture of
3-iodo-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[-
3,4-c]pyridine and
3-iodo-5-(pyridin-3-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-pyrazolo[-
3,4-c]pyridine as a white solid (50 g, 35%)
Example 6
5-bromo-1H-pyrazolo[3,4-c]pyridine
##STR00444##
[0171] To a solution of 6-bromo-4-methylpyridin-3-amine (7.76 g,
0.0415 mol) in acetic acid (412.8 mL, 7.260 mol) was added Sodium
nitrite (2.87 g, 0.0416 mol) in 4.0 ml water (Bioorg. Med. Chem. 15
(2007) 2441-2452). The reaction was stirred for 15 min and allowed
to stand at room temperature (rt) for 2 days (d). The reaction was
concentrated and diluted EtOAc then washed with NaHCO.sub.3 and
brine. The organic layer was dried Na.sub.2SO.sub.4, filtered and
concentrated. The crude was purified by chromatography (DCM/MeOH)
eluted at 5% MeOH) to give 5-bromo-1H-pyrazolo[3,4-c]pyridine
(79.1% yield)
Example 7
5-bromo-3-iodo-1H-pyrazolo[3,4-c]pyridine
##STR00445##
[0173] A solution containing 5-bromo-1H-pyrazolo[3,4-c]pyridine
(168.0 g, 848.4 mmol) and NIS (286.3 g, 1.27 mol) in DMF (1.2 L)
was stirred on at room temperature. The reaction mixture was poured
into water then filtered. The solid was washed with water and 5%
Na.sub.2S.sub.2O.sub.5. The crude product was dried under high
vacuum overnight to give
5-bromo-3-iodo-1H-pyrazolo[3,4-c]pyridine.
Example 8
5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine
##STR00446##
[0175] To a solution of Bromo-iodo-azaindazole (50 g, 154.36 mmol)
in Methylene chloride (500 mL) was added Dihydropyran (28.57 g,
339.59 mmol) and TsOH (2.06 g, 10.81 mmol). The reaction was
stirred at 20.degree. C. overnight. LCMS showed that the reaction
was complete, then the reaction was quenched with saturated
NaHCO.sub.3. The organic layer was dried and concentrated to give
crude product which was purified by silica gel chromatography to
afford
5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine
(40 g, 71%) as a pale yellow solid.
Example 9
Bromo-3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,-
4-c]pyridine
##STR00447##
[0177] A mixture of 2.0 g (4.90 mmol) of
5-bromo-3-iodo-1H-pyrazolo[3,4-c]pyridine, 2.0 g (5.17 mmol) of
2-Fluoro-6-tributylstannanyl-pyridine and 566.4 mg (0.4902 mmol) of
Tetrakis(triphenylphosphine)palladium(0) in 45 ml of Toluene was
degassed an heated at 120.degree. C. for 24 hours. Clear solution
was concentrated in vacuum; the crystalline residue was mixed with
30 ml of ethyl ether and stirred for 20 min. The yellow precipitate
was filtered out, washed with ether and dried on air to give
bromo-3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3-
,4-c]pyridine. Yield 1.356 g (71%). ESI MS m/z=377.0, 378.9
(doublet, M+1)
Example 10
3-(6-Fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H--
pyrazolo[3,4-c]pyridine
##STR00448##
[0179] A mixture of 1.356 g (3.60 mmol) of
5-bromo-3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo-
[3,4-c]pyridine, 3.445 g, (16.80 mmol) of 3-pyridineboronic acid
pinacol ester and 0.457 g (0.560 mmol) of
1,1'bis(diphenylphosphino)ferrocenepalladium (II) chloride and 7.2
ml of 1.0 M of Cesium Carbonate in water in 60 ml of Acetonitrile
was degassed an heated in a sealed glass vial at 95.degree. C. for
2 hours. The mixture was filtered through Celite and the filtrate
concentrated in vacuum. The residue was redissolved in
dichloromethane, the organic layer washed with water, brine, dried
over MgSO4 and concentrated. The crude residue was purified on a 80
g silica gel column eluting with 3-4% of methanol in
dichloromethane. Pooled fractions were concentrated. The residue
was triturated with 7 ml of cold methanol and filtered to give
3-(6-Fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-
-pyrazolo[3,4-c]pyridine. Yield 1.147 g (85%). ESI MS m/z=376.1
(M+1)
Example 11
5-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine
##STR00449##
[0181] To a solution of 5-bromo-1H-pyrazolo[3,4-c]pyridine (100 mg,
0.5 mmol) in DME:EtOH (5:1, 5 mL) was added Pd(dppf) Cl.sub.2 (20
mg), saturated solution of Na.sub.2CO.sub.3 (1 mL) and
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (116
mg, 0.6 mmol). Under argon, the mixture was stirred under microwave
irradiation for 60 min at 150. After cooling down, the solvent was
removed under reduced pressure and the residue was purified by
silica-gel column chromatography (mobile phase: EA:PE=1:1) to
afford 5-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine (40 mg, 43%).
.sup.1H NMR (500 MHz, MeOD) .delta. 9.17 (s, 1H), 8.98 (s, 1H),
8.17 (m, 3H), 8.05 (d, J=1.5, 1H). ESI MS m/z=186.1 (M+1).
Example 12
5-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine (P2-040)
##STR00450##
[0183] To a solution of 5-bromo-1H-pyrazolo[3,4-c]pyridine (100 mg,
0.5 mmol) in DME:EtOH (5:1, 5 mL) was added Pd(dppf) Cl.sub.2 (20
mg), saturated solution of Na.sub.2CO.sub.3 (1 mL) and
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (116
mg, 0.6 mmol). Under argon the mixture was stirred under microwave
irradiation at 150.degree. C. for 60 min. After cooling down, the
solvent was removed under reduced pressure and the residue was
purified by silica-gel column chromatography (mobile phase:
EA:PE=1:1) to afford 5-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine
(20 mg, 22%). .sup.1H NMR (500 MHz, MeOD) .delta. 9.05 (s, 1H),
8.24 (m, 2H), 7.75 (s, 1H), 6.89 (s, 1H). ESI MS m/z=186.1
(M+1)
Table 1 Formula I Compounds
Example 101
3-methyl-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine 101
Step 1: 5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine
##STR00451##
[0185] To a solution of 5-bromo-1H-pyrazolo[3,4-c]pyridine from
Example 6 (100 mg, 0.5 mmol) in DMF (5 mL) was added Pd(dppf)
Cl.sub.2 (20 mg), saturated solution of Na.sub.2CO.sub.3 (1 mL) and
pyridin-3-ylboronic acid (74 mg, 0.6 mmol). The mixture was stirred
under argon for 16 h at 80.degree. C. After cooling down, the
solvent was removed under reduced pressure and the residue was
purified by silica-gel column chromatography (mobile phase:
EA:PE=1:1) to afford 5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine
(59 mg, 60%). .sup.1H NMR (500 MHz, MeOD) .delta. 9.17 (s, 1H),
9.09 (s, 1H), 8.52 (d, J=3.5, 1H), 8.44 (q, J=7, 2, 1H), 8.29 (d,
J=5, 1H), 8.23 (s, 1H), 7.53 (q, J=9.5, 5.5, 1H). ESI MS m/z=197.1
(M+1).
Step 2: 3-Bromo-1H-pyrazolo[3,4-c]pyridine
##STR00452##
[0187] 1H-pyrazolo[3,4-c]pyridine (1 g), bromine (1.33 g), and
water (40 mL) were stirred for 1 h. Basification with 20% sodium
hydroxide solution, and adjustment to pH 7 by addition of acetic
acid, yielded 3-Bromo-1H-pyrazolo[3,4-c]pyridine (1.1 g, 67%). ESI
MS m/z=275 (M+1)
Step 3
[0188] To a solution of 90 mg (0.6 mmol) of
9-methoxy-9-bora-bicyclo[3.3.1]nonane in 5 mL of anhydrous
tetrahydrofuran was added dropwise 0.37 mL (0.6 mmol) of a solution
1 N of methyl lithium in diethylether. After few minutes of
stirring, a mixture of 3-bromo-1H-pyrazolo[3,4-c]pyridine (0.16 g,
0.6 mmol), and 10 mg (0.015 mmol) of bis(triphenylphosphine)
palladium(II) dichloride in 10 mL of anhydrous tetrahydrofuran was
added. The reaction mixture was stirred in a microwave oven at
150.degree. C. for 15 minutes. After filtration over celite and
concentration in vacuo, the residue is purified by flash
chromatography (SiO.sub.2, PE/ethyl acetate 1:1) to afford 47 mg of
101 (37%). .sup.1H NMR (500 MHz, DMSO-d6) .delta. 9.34 (d, J=2,
1H), 9.09 (s, 1H), 8.57 (dd, J=4.5, 1.5, 1H), 8.48 (d, J=7.5, 1H),
8.44 (s, 1H), 7.51 (q, J=8, 5, 1H), 2.60 (s, 3H). ESI MS m/z=211.1
(M+1)
Example 102
3-methyl-5-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine 102
Step 1: 1-(2-bromo-5-fluoropyridin-4-yl)ethanol
##STR00453##
[0190] To a 1000 mL 3-neck flask was added 2-bromo-5-fluoropyridine
(8.80 g, 50 mmol) and THF (200 mL) at -78.degree. C. followed by
dropwise addition of LDA (20.0 mL, 50 mmol, 2.5 M). After stirring
at -78.degree. C. for 4 h, acetaldehyde (3.1 mL, 55 mmol) was added
dropwise via syringe. The contents were removed from the cold bath
and stirred at room temperature overnight. The mixture was diluted
with H2O (150 mL), and vigorously stirred for 5 min. The contents
were extracted with ethyl ether (3.times.150 mL), the combined
organic layers were dried over MgSO4, filtered, and concentrated in
vacuo to afford a yellow oil. The crude product was passed through
a short silica column (eluent: 3:1 PE/EtOAc) to afford
1-(2-bromo-5-fluoropyridin-4-yl)ethanol as a white solid (9.5 g,
86%). ESI MS m/z=220 (M+1)
Step 2: 1-(2-bromo-5-fluoropyridin-4-yl)ethanone
##STR00454##
[0192] To a 350 mL sealed flask was dissolved
1-(2-bromo-5-fluoro-4-pyridinyl)ethanol (9.4 g, 42.3 mmol) in 60 mL
dry CHCl3. Added next to the stirring solution was
manganese(IV)oxide (14.7 g, 169 mmol). The vigorously stirred
contents were sealed and heated at 95.degree. C. for 2.5 h. After
cooling to room temperature, the black heterogeneous mixture was
vacuum filtered through a pad of Celite, and the filter pad washed
with CH2Cl2 (10 mL). The yellow colored filtrate was concentrated
in vacuo to a yellow oil, which was purified by silica gel column
chromatography (eluent: 9:1 PE/EtOAc) to afford
1-(2-bromo-5-fluoropyridin-4-yl)ethanone as a pale yellow oil (8.2
g, 88%). ESI MS m/z=218 (M+1)
Step 3: 5-Bromo-3-methyl-1H-pyrazolo[3,4-c]pyridine
##STR00455##
[0194] To a 150 mL sealed flask containing 50 mL dry ethylene
glycol was dissolved 1-(2-bromo-5-fluoro-4-pyridinyl)ethanone (8.2
g, 37.6 mmol). Added dropwise via syringe next was anhydrous
hydrazine (1.24 mL, 39.5 mmol). The stirred light yellow mixture
was sealed, and heated at 165.degree. C. After 3.5 h, the
orange-tan reaction mixture was removed from heating. After cooling
to room temperature, the contents were poured onto a stirring
mixture of 300 g ice/water (1:1), wherein solid precipitation
occurred. After stirring for 10 min, the off-white precipitate was
collected. This solid was dried in vacuo and collected
5-Bromo-3-methyl-1H-pyrazolo[3,4-c]pyridine as an off-white solid
(7.9 g, 99%). ESI MS m/z=212 (M+1).
Step 4
[0195] To a solution of 5-bromo-3-methyl-1H-pyrazolo[3,4-c]pyridine
(106 mg, 0.5 mmol) in DMF (5 mL) was added Pd(dppf) Cl.sub.2 (20
mg), saturated solution of Na.sub.2CO.sub.3 (1 mL) and
1H-pyrazol-4-ylboronic acid (67 mg, 0.6 mmol). Under argon, the
mixture was stirred under microwave irradiation for 1 h at
150.degree. C. After cooling down, the solvent was removed under
reduced pressure and the residue was purified by silica-gel column
chromatography (mobile phase: EA:PE=1:1) to afford 102 (15 mg,
15%). .sup.1H NMR (500 MHz, MeOD) .delta. 8.88 (s, 1H), 8.16 (m,
2H), 8.00 (s, 1H), 2.61 (s, 3H); ESI MS m/z=200.1 (M+1)
Example 103
3-methyl-5-(1H-pyrazol-5-yl)-1H-pyrazolo[3,4-c]pyridine 103
[0196] To a solution of 5-Bromo-3-methyl-1H-pyrazolo[3,4-c]pyridine
from Example 102 (106 mg, 0.5 mmol) in DMF (5 mL) was added
Pd(dppf) Cl.sub.2 (20 mg), saturated solution of Na.sub.2CO.sub.3
(1 mL) and 1H-pyrazol-3-ylboronic acid (67 mg, 0.6 mmol). The
mixture was stirred under argon for 16 h at 80.degree. C. After
cooling down, the solvent was removed under reduced pressure and
the residue was purified by silica-gel column chromatography
(mobile phase: EA:PE=1:1) to afford 103 (15 mg, 15%). .sup.1H NMR
(500 MHz, MeOD) .delta. 8.96 (s, 1H), 8.23 (s, 1H), 7.71 (s, 1H),
6.90 (d, J=1.5, 1H), 2.65 (s, 3H). ESI MS m/z=200.1 (M+1)
Example 115
3-methyl-5-(pyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridine 115
##STR00456##
[0198] In a microwave reaction vials was charged with
5-bromo-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine
(296 mg, 1.0 mmol), Pyrimidine-5-boronic acid (185 mg, 1.5 mmol),
1,1'-Bis(diphenylphosphino)ferrocenepalladium (II) chloride (81.7
mg, 0.1 mmol), 1.00 M of Potassium acetate in Water (1.5 mL, 1.5
mmol), 1.00 M of Sodium carbonate in Water (1.5 mL, 1.5 mmol), and
Acetonitrile (10 mL). The reaction mixture was heated under
microwave at 130.degree. C. for 30 minutes. The mixture was
concentrated and the residue was purified on silica eluted with 0
to 5% MeOH in DCM with 1% NH4OH to afford
3-methyl-5-(pyrimidin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4--
c]pyridine (281.9 mg, 95.45%).
[0199] A solution of
3-methyl-5-(pyrimidin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4--
c]pyridine (281.2 mg, 0.9521 mmol) in 4.0 M of Hydrogen chloride in
1,4-Dioxane (5 mL) and 1,4-Dioxane (5 mL, 60 mmol) was stirred at
room temperature overnight. The reaction mixture was concentrated
and the residue was purified by reverse phase HPLC to afford 115 as
an off-white solid (73.30 mg, 37%). 1H NMR (400 MHz, DMSO) .delta.
13.39 (s, 1H), 9.50 (s, 2H), 9.18 (s, 1H), 9.11 (d, J=1.1 Hz, 1H),
8.56 (d, J=1.2 Hz, 1H), 2.60 (s, 3H); ESI MS m/z=212.1 (M+1)
Example 116
3-phenyl-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine 116
[0200] To a solution of
3-iodo-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine from Example 4
(161 mg, 0.5 mmol) in DME:EtOH (5:1, 5 mL) was added Pd(dppf)
Cl.sub.2 (20 mg), saturated solution of Na.sub.2CO.sub.3 (1 mL) and
phenylboronic acid (74 mg, 0.6 mmol). The mixture was heated in
argon under microwave radiation at 135 for 60 min. After cooling
down, the solvent was removed under reduced pressure and the
residue was purified by silica-gel column chromatography (mobile
phase: EA:PE=1:1) to afford 116 (82 mg, 60%). .sup.1H NMR (400 MHz,
DMSO) .delta. 9.33 (s, 1H), 9.21 (s, 1H), 8.56 (s, 1H), 8.53-8.51
(m, 2H), 8.12-8.10 (m, 2H), 7.57-7.44 (m, 4H).; ESI MS m/z=273.7
(M+1
Example 117
3-(2-fluorophenyl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine
117
[0201] Following the procedures as described in Example 116,
3-iodo-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine from Example 4
and 2-fluorophenylboronic acid were converted to 117 as a yellow
solid (86 mg, 56%) over two steps. .sup.1H NMR (400 MHz, DMSO)
.delta. 9.32 (s, 1H), 9.25 (s, 1H), 8.59-8.58 (m, 1H), 8.48-8.47
(m, 1H), 8.35 (s, 1H), 7.94-7.91 (m, 1H), 7.59-7.54 (m, 4H).; ESI
MS m/z=291.7 (M+1)
Example 118
3-methyl-5-(pyrazin-2-yl)-1H-pyrazolo[3,4-c]pyridine 118
[0202] Following the procedures as described in Example 115 and
starting with
2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine, 118 was
obtained as an off-white solid (3.10 mg, 13%) over two steps. 1H
NMR (400 MHz, DMSO) .delta. 13.42 (s, 1H), 9.56 (d, J=1.3 Hz, 1H),
9.11 (s, 1H), 8.73-8.70 (m, 2H), 8.64 (d, J=2.5 Hz, 1H), 2.61 (s,
3H); ESI MS m/z=212.1 (M+1)
Example 122
5-(3-fluorophenyl)-3-methyl-1H-pyrazolo[3,4-c]pyridine 122
[0203] Under nitrogen protection, to 6 mL of dioxane was added
5-bromo-3-methyl-1H-pyrazolo[3,4-c]pyridine from Example 102 (0.21
g, 1 mmol), 3-fluorophenylboronic acid (0.28 g, 2 mmol),
PdCl.sub.2(dppf) (87 mg, 0.1 mmol) and 2 M Na.sub.2CO.sub.3 (2
mmol, 1 mL). The suspension was heated under microwave radiation at
130.degree. C. for 1 hour. It was cooled to room temperature and
the solvent was removed the solvent. The crude product was purified
by SGC (EtOAc/Petroleum: 1/1) to afford 79 mg (34%) of 122 as a
white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 9.12 (s,
1H), 7.98 (s, 1H), 7.75-7.82 (m, 2H), 7.44-7.47 (m, 1H), 7.08-7.09
(m, 1H), 2.67 (s, 3H). ESI MS m/z=229 (M+1)
Example 123
5-(5-fluoropyridin-3-yl)-3-methyl-1H-pyrazolo[3,4-c]pyridine
123
[0204] To a mixture of
5-bromo-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine
(90.0 mg, 0.304 mmol), 5-fluoropyridin-3-ylboronic acid (128.6 mg,
0.9124 mmol) and 1,1'-Bis(diphenylphosphino)ferrocenepalladium (II)
chloride (37.2 mg, 0.0456 mmol) in Acetonitrile (2.86 mL, 54.7
mmol) was added 1.0 M of Potassium acetate in Water (0.456 mL) and
1.0 M of Sodium carbonate in Water (0.456 mL). The reaction mixture
was irradiated in microwave at 125.degree. C. for 20 min. The
reaction was filtered thru celite and concentrated. The crude
product was purified by silica gel column using ethyl
acetate/heptane to give
5-(5-fluoropyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-
o[3,4-c]pyridine which was dissolved in 12M HCl (1.30 mL, 15.6
mmol) and Methanol (13.0 mL). The reaction mixture was stirred at
RT (room temperature) for 18 h. The reaction was concentrated and
then submitted for rHPLC to give 123 (27.9 mg, 40.2% yield). ESI MS
m/z=229.1 (M+1). .sup.1H NMR (400 MHz, DMSO) .delta. 9.25 (s, 1H),
9.08 (s, 1H), 8.62-8.49 (m, 2H), 8.47-8.30 (m, 1H), 2.60 (s,
3H)
Example 126
5-(pyridin-3-yl)-3-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-c]pyridine
126
[0205] Following the Suzuki coupling procedure of Example 159,
5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine
and 3-(trifluoromethyl)phenylboronic acid were reacted and the
product was consequently reacted under Suzuki coupling procedure of
Example 10 with 3-pyridineboronic acid pinacol ester and
deprotected by the procedure of Example 131. The mixture was
obtained as a base and purified by crystallization from ethyl
acetate to afford 56 mg (33%) of 126 over three steps. ESI MS m/z
341.1 (M+1)
Example 127
3-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine
127
[0206] In a microwave vial was charged with tert-butyl
5-bromo-3-methyl-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (53 mg,
0.17 mmol),
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazo-
le (70.6 mg, 0.34 mmol), potassium acetate (205.5 mg, 2.09 mmol),
cesium carbonate (166.0 mg, 0.51 mmol), and
bis(diphenylphosphino)ferrocene]dichloropalladium (II), complexed
with dichloromethane (1:1) (13.9 mg, 0.017 mmol). DMF (2.6 mL) and
water (0.5 mL) were added. Nitrogen was passed through the mixture
for 15 minutes and the vial was capped. The reaction mixture was
subjected to microwave irradiation at 125.degree. C. for 20 min.
The reaction mixture was filtered through a pad of Celite.RTM. and
diluted with water and EtOAc. The organic layer was washed with
brine, dried over Na.sub.2SO.sub.4, filtered, and evaporated in
vacuo. The crude product was purified using flash chromatography
(Si-PPC gradient elution, solvent: 50-100% ethyl acetate in
heptanes, followed by 0-30% methanol in ethyl acetate) to give 127
as a foam (26.0 mg, 71.8%). .sup.1H NMR (400 MHz, DMSO) .delta.
13.08 (broad s, 1H), 8.90 (s, 1H), 8.19 (s, 1H), 7.98 (s, 1H), 7.94
(s, 1H), 3.88 (s, 3H), 2.53 (s, 3H). LC/MS: m/z 214.1 [M+1]
Example 129
3-(2-fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine
129
Step 1:
3-(2-Fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-p-
yran-2-yl)-1H-pyrazolo[3,4-c]pyridine
##STR00457##
[0208] Following the procedures in Example 133, using
2-fluorobenzylboronic acid in place of phenylboronic acid,
3-(2-Fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2--
yl)-1H-pyrazolo[3,4-c]pyridine was obtained as a foam (50.7% over
two steps). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.15 (s, 1H),
7.97 (d, J=5.6 Hz, 2H), 7.90-7.81 (m, 2H), 7.45 (ddd, J=7.3, 6.3,
1.7 Hz, 1H), 7.30 (dd, J=9.2, 5.9 Hz, 1H), 7.25 (d, J=6.6 Hz, 1H),
5.90 (dd, J=8.8, 2.5 Hz, 1H), 4.06 (dd, J=11.8, 4.1 Hz, 1H), 3.97
(s, 3H), 3.87-3.76 (m, 1H), 2.63-2.51 (m, 1H), 2.19 (d, J=9.5 Hz,
2H), 1.89-1.68 (m, 3H). LC/MS: m/z 378.3 [M+1]
Step 2
[0209] Following the procedure as described in Example 133,
3-(2-fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2--
yl)-1H-pyrazolo[3,4-c]pyridine in place of
5-(1-methyl-1H-pyrazol-4-yl)-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyr-
azolo[3,4-c]pyridine was converted to 129 as a white solid (69.1%).
.sup.1H NMR (400 MHz, DMSO) .delta. 13.95 (broad s, 1H), 9.06 (s,
1H), 8.26 (s, 1H), 7.99 (s, 1H), 7.91 (d, J=1.8 Hz, 1H), 7.89-7.82
(m, 1H), 7.54 (dd, J=13.2, 6.2 Hz, 1H), 7.47-7.35 (m, 2H), 3.87 (s,
3H). LC/MS: m/z 294.0 [M+1]
Example 131
3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine
131
[0210] To a mixture of 120 mg (0.32 mmol) of
3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-
-pyrazolo[3,4-c]pyridine from Example 10 in 3 ml of methanol, 12 ml
of 4N HCl in dioxane was added. The mixture was stirred for 8 hours
and concentrated in vacuum. The residue was triturated with ethyl
ether. The solid material was filtered out, washed with ethyl ether
and dried. The above solid was dispersed in 30 ml of saturated
aqueous sodium bicarbonate and the suspension was stirred for 1
hour. The solid base was collected, washed with water and dried in
high vacuum for 24 hours to yield 95 mg of 131 (90%). ESI MS m/z
292.1 (M+1). 1H NMR (400 MHz, DMSO): 9.32-9.21 (m, 1H), 8.81 (s,
1H), 8.61 (dd, J=4.7, 1.4 Hz, 1H), 8.42 (d, J=8.0 Hz, 1H),
8.21-8.06 (m, 1H), 7.55 (dd, J=7.9, 4.7 Hz, 1H), 7.18 (d, J=7.7 Hz,
1H), 6.53 (s, 1H), 6.28 (s, 1H)
Example 132
6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2(1H)-one
132
[0211] A mixture of 58.2 mg (0.200 mmol) of
3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine
was heated in 15 ml of 1 N aq HCl for 4 hours. The product
crystallized upon cooling. The precipitate was collected, washed
with water and dried in high vacuum to give 132. Yield 48 mg (83%).
ESI MS m/z 290.0 (M+1). 1H NMR (400 MHz, DMSO): 14.18 (s, 1H), 9.54
(s, 1H), 9.26 (s, 1H) 9.15 (s, 1H), 8.94 (d, J=6.5 Hz, 1H), 8.77
(d, J=5.0 Hz, 1H), 7.86 (s, 1H), 7.74 (t, J=7.7 Hz, 1H), 7.52 (s,
1H), 6.62 (d, J=8.2 Hz, 1H)
Example 133
5-(1-methyl-1H-pyrazol-4-yl)-3-phenyl-1H-pyrazolo[3,4-c]pyridine
133
Step 1:
5-bromo-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]py-
ridine
##STR00458##
[0213] In an oven-dried flask was placed
5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine
(2.0 g, 4.90 mmol), phenylboronic acid (627.5 mg, 5.15 mmol), and
bis(diphenylphosphino)ferrocene]dichloropalladium (II), complexed
with dichloromethane (1:1) (200.14 mg, 0.24 mmol). Degassed
acetonitrile (53 mL) was added, followed by 1.0 M aqueous sodium
carbonate solution (7.4 mL) and 1.0 M aqueous potassium acetate
solution (7.4 mL). The reaction mixture was degassed under N.sub.2
for 5 minutes more and stirred at 80.degree. C. under N.sub.2 for 1
h. The reaction mixture was cooled to room temperature, partitioned
between EtOAc and water and the layers were separated. The organic
layer was washed with water (3.times.) and brine, dried over
Na.sub.2SO.sub.4 and concentrated to an oil. The crude product was
purified using flash column chromatography (Si-PPC gradient
elution, solvent: 0-60% ethyl acetate in heptanes) to give
5-bromo-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine
as a solid (1.45 g, 82.47%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.95 (d, J=0.9 Hz, 1H), 8.08 (d, J=0.9 Hz, 1H), 7.94-7.88
(m, 2H), 7.55-7.48 (m, 2H), 7.48-7.41 (m, 1H), 5.86 (dd, J=8.6, 2.6
Hz, 1H), 4.07-3.97 (m, 1H), 3.80 (ddd, J=12.3, 8.9, 3.8 Hz, 1H),
2.54 (qd, J=9.0, 5.5 Hz, 1H), 2.24-2.11 (m, 2H), 1.89-1.67 (m, 3H).
LC/MS: m/z 274.1 (des-THP) [M+1]
Step 2:
5-(1-Methyl-1H-pyrazol-4-yl)-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-
-1H-pyrazolo[3,4-c]pyridine
##STR00459##
[0215] In a microwave vial was charged with
5-bromo-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine
(500 mg, 1.39 mmol),
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(435.6 mg, 2.09 mmol), potassium acetate (205.5 mg, 2.09 mmol),
sodium carbonate (221.9 mg, 2.09 mmol), and
bis(diphenylphosphino)ferrocene]dichloropalladium (II), complexed
with dichloromethane (1:1) (108.3 mg, 0.13 mmol). Degassed
acetonitrile (10.5 mL) and water (2.6 mL) were added. Nitrogen was
passed through the mixture for 15 minutes and the vial was capped.
The reaction mixture was subjected to microwave irradiation at
125.degree. C. for 25 min. The reaction mixture was filtered
through a pad of Celite.RTM. and diluted with water and EtOAc. The
organic layer was washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated under reduced pressure. The crude
product was purified using flash chromatography (Si-PPC gradient
elution, solvent: 60-100% ethyl acetate in heptanes, followed by
0-30% methanol in ethyl acetate) to give
5-(1-methyl-1H-pyrazol-4-yl)-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyr-
azolo[3,4-c]pyridine as a foam (340.0 mg, 67.8%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 9.15 (s, 1H), 8.07-7.94 (m, 5H), 7.54 (t,
J=7.6 Hz, 2H), 7.45 (t, J=7.4 Hz, 1H), 5.88 (dd, J=8.8, 2.2 Hz,
1H), 4.06 (dd, J=11.8, 4.0 Hz, 1H), 3.98 (s, 3H), 3.86-3.76 (m,
1H), 2.66-2.52 (m, 1H), 2.19 (d, J=10.8 Hz, 2H), 1.89-1.67 (m, 3H).
LC/MS: m/z 378.3 [M+1]
Step 3
[0216] To a stirred solution of
5-(1-methyl-1H-pyrazol-4-yl)-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyr-
azolo[3,4-c]pyridine (54.5 mg, 0.152 mmol) in MeOH (8 mL) was added
6 M HCl in water. The reaction mixture was stirred at 60.degree. C.
under N.sub.2 for 16 h. The reaction mixture was cooled to room
temperature. Volatile solvent was removed under reduced pressure.
The crude was redissolved in EtOAc. The organic layer was washed
with saturated aqueous sodium bicarbonate solution, water and
brine, dried over Na.sub.2SO.sub.4, filtered, and evaporated in
vacuo. Crystallization from DCM-heptanes afforded 133 as a solid
(40 mg, 95.8%). .sup.1H NMR (400 MHz, DMSO) .delta. 13.71 (broad s,
1H), 9.04 (s, 1H), 8.32 (s, 1H), 8.24 (s, 1H), 8.09 (d, J=7.3 Hz,
3H), 7.55 (t, J=7.5 Hz, 2H), 7.44 (t, J=7.4 Hz, 1H), 3.90 (s, 3H).
LC/MS: m/z 276.1 [M+1]
Example 136
3-(2-fluorophenyl)-5-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine
136
[0217] A microwave tube charged with
5-bromo-3-(2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c-
]pyridine (376 mg, 1 mmol), 1H-pyrazol-4-ylboronic acid (224 mg, 2
mmol), Pd(dppf) Cl.sub.2 (50 mg, 0.0625 mmol), saturated solution
of Na.sub.2CO.sub.3 (0.5 mL), and DME/EtOH (5 mL/0.5 mL) was
irradiated under microwave at 140.degree. C. for 1 h. After cooling
down, ethyl acetate was added. The mixture was washed with water
twice (2.times.20 mL), dried over anhydrous Na.sub.2SO.sub.4 and
concentrated to afford the crude product. The crude product was
purified by silica-gel column chromatography eluting with 50% ethyl
acetate in heptane to afford
3-(2-fluorophenyl)-5-(1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-py-
razolo[3,4-c]pyridine as a white solid (300 mg, 82%, ESI MS m/z=364
(M+1) which was treated with HCl/dioxane (4 mL, 3 mol/L) and
stirred for overnight. The crude product was received by filtration
and washed with a little dioxane. It was further purified by
prep-HPLC eluting with 5 to 95% CH.sub.3CN in aqueous 10 mmol
NH.sub.4HCO.sub.3 solution to afford 136 as a white solid (180 mg,
72%). .sup.1H NMR (400 MHz, DMSO) .delta. 9.02 (s, 1H), 8.16 (s,
2H), 8.02 (m, 1H), 7.87 (m, 1H), 7.54 (m, 1H), 7.38 (m, 2H). ESI MS
m/z=280 (M+1)
Example 137
3-phenyl-5-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine 137
[0218] Following the procedures as described in Example 136,
1H-pyrazol-4-ylboronic acid and
5-bromo-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine
were reacted and the product was deprotected to give 137 as a
yellow solid (26 mg, 23%) over two steps. .sup.1H NMR (400 MHz,
DMSO) .delta. 12.9 (s, 1H), 9.05 (s, 1H), 8.37-8.09 (m, 5H), 7.56
(m, 1H), 7.44 (m, 1H)
Example 138
3-(2-fluorophenyl)-5-(pyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridine
138
[0219] Following the procedures as described in Example 136,
pyrimidin-5-ylboronic acid and
3-(2-fluorophenyl)-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4--
c]pyridine were reacted and the product was deprotected to give 138
as a white solid (25 mg, 25%) over two steps. .sup.1H NMR (400 MHz,
DMSO) .delta. 14.2 (s, 1H), 9.51 (s, 2H), 9.28 (s, 1H), 9.21 (s,
1H), 8.50 (s, 1H), 7.92 (mt, 2H), 7.59 (t, 2H), 7.41 (t, 1H). ESI
MS m/z=292 (M+1)
Example 142
3-phenyl-5-(1H-1,2,4-triazol-1-yl)-1H-pyrazolo[3,4-c]pyridine
142
##STR00460##
[0221] Following the procedures of Examples 146 and 131,
5-bromo-3-phenyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine
and 1,2,4-triazole were reacted to give 142 as a white solid (20
mg, 27%) over two steps. ESI MS m/z 263.0 (M+1). 1H NMR (400 MHz,
DMSO): 14,32 (s, 1H), 9.36 (s, 1H), 9.09 (d, J=1.0 Hz, 1H), 8.38
(d, J=1.0 Hz, 1H), 8.30 (s, 1H), 8.07-8.00 (m, 2H), 7.60 (t, J=7.6
Hz, 2H), 7.48 (t, J=7.4 Hz, 1H)
Example 143
N1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)ethane-
-1,2-diamine 143
##STR00461##
[0223] A mixture of 56.3 mg (0.150 mmol) of
3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-
-pyrazolo[3,4-c]pyridine and 1.0 ml (15.0 mmol) of
1,2-ethylenediamine was heated at 160.degree. C. for 30 min. The
mixture was mixed with water and extracted with ethyl acetate. The
organic extracts were washed with water 3 times, brine, dried over
MgSO4 and concentrated. The residue was heated in a mixture of 4 M
of hydrogen chloride in 6 ml of dioxane and 2 ml of conc.
hydrochloric acid at 60.degree. C. for 18 hours. The mixture was
concentrated in high vacuum and triturated with ethyl ether. The
solid material was filtered out and washed with ethyl ether to give
143. Yield 37.5 mg (56%) over two steps. ESI MS m/z 332.1 (M+1). 1H
NMR (400 MHz, DMSO): 14.27 (s, 1H), 9.57 (s, 1H), 9.30 (s, 1H),
9.19 (d, J=8.0 Hz, 1H), 9.11 (s, 1H), 8.90 (d, J=4.8 Hz, 1H), 8.23
(s, 3H), 8.11 (dd, J=7.9, 5.6 Hz, 1H), 7.68 (d, J=7.5 Hz, 1H), 7.53
(d, J=7.2 Hz, 1H), 6.71 (d, J=7.3 Hz, 1H), 3.75 (t, J=6.0 Hz, 2H),
3.17 (dd, J=11.4, 5.7 Hz, 2H)
Example 144
1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperid-
in-4-amine 144
[0224] A mixture of 56.3 mg (0.150 mmol) of
3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-
-pyrazolo[3,4-c]pyridine and 211 mg, 0.90 mmol) of benzyl
piperidin-4-ylcarbamate in 1.0 ml of dimethyl sulfoxide was heated
at 100.degree. C. for 24 hours. The mixture was mixed with water
and extracted with ethyl acetate. The organic extracts were washed
with water, 1% aqueous citric acid, water, brine, dried over MgSO4
and concentrated. The residue was heated in a mixture of 4 M of
hydrogen chloride in 6 ml of dioxane and 2 ml of cone. hydrochloric
acid at 60.degree. C. for 18 hours. The mixture was concentrated in
high vacuum and triturated with ethyl ether. The solid material was
filtered out and washed with ethyl ether to give 144. Yield 13.7 mg
(19%) over two steps. ESI MS m/z 372.1 (M+1). 1H NMR (400 MHz,
DMSO): 14.17 (s, 1H), 9.41 (s, 1H), 9.29 (s, 1H), 8.99 (s, 1H),
8.93 (d, J=7.9 Hz, 1H), 8.87 (d, J=5.0 Hz, 1H), 8.14 (s, 3H),
8.07-7.99 (m, 1H), 7.76-7.69 (m, 1H), 7.51 (d, J=7.4 Hz, 1H), 6.99
(d, J=8.5 Hz, 1H), 4.52 (d, J=13.3 Hz, 3H), 3.40 (s, 2H), 3.12 (t,
J=11.9 Hz, 2H), 2.08 (d, J=10.1 Hz, 2H), 1.66 (dt, J=12.0, 8.5 Hz,
2H)
Example 146
5-(1H-imidazol-1-yl)-3-phenyl-1H-pyrazolo[3,4-c]pyridine 146
[0225] A mixture of 100.0 mg (0.2791 mmol) of
5-bromo-3-phenyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine,
47.51 mg (0.6979 mmol) of 1H-Imidazole, 53.16 mg (0.2791 mmol) of
Copper(I) iodide, 30.04 uL (0.2791 mmol) of
N,N'-dimethylethylenediamine and 363.8 mg (1.116 mmol) of Cesium
Carbonate in 3 ml of N,N-Dimethylformamide was heated at
120.degree. C. for 48 hours. The mixture was filtered, the filtrate
concentrated in high vacuum and the residue partitioned between
ethyl acetate and water. The organic extracts were washed with
water, brine, dried over MgSO4 and concentrated in vacuum. The
residue was purified on 4 g of silica gel column, eluting
5-(1H-imidazol-1-yl)-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,-
4-c]pyridine with a gradient of ethyl acetate in heptane. Yield 67
mg (69%). ESI MS m/z 346.1 (M+1).
[0226] Deprotection of
5-(1H-imidazol-1-yl)-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,-
4-c]pyridine (67 mg, 0.193 mmol) yielded 60 mg of the crude
hydrochloride salt product which was purified via reverse phase
HPLC using a gradient of MeOH in water with 0.1% NH.sub.4OH to
afford 25 mg (49%) of 146 as a white solid. ESI MS m/z 262.0 (M+1).
1H NMR (400 MHz, DMSO): 13.89 (s, 1H), 9.05 (d, J=0.9 Hz, 1H), 8.59
(s, 1H), 8.34 (d, J=1.1 Hz, 1H), 8.16-8.11 (m, 2H), 8.09 (t, J=1.3
Hz, 1H), 7.57 (t, J=7.6 Hz, 2H), 7.46 (t, J=7.4 Hz, 1H), 7.13 (s,
1H)
Example 149
(R)-1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pip-
eridin-3-amine 149
[0227] Following the procedure of Example 144,
3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-
-pyrazolo[3,4-c]pyridine and (R)-benzyl piperidin-3-ylcarbamate
were reacted to give 17 mg of 149 (15% over two steps). ESI MS m/z
372.1 (M+1). 1H NMR (400 MHz, DMSO): 14.24 (s, 1H), 9.49 (s, 1H),
9.30 (s, 1H), 9.10 (d, J=8.3 Hz, 1H), 9.06 (s, 1H), 8.36 (s, 3H),
8.21-8.12 (m, 1H), 7.78-7.72 (m, 1H), 7.56 (d, J=7.4 Hz, 1H), 6.99
(d, J=8.5 Hz, 1H), 4.49 (d, J=11.3 Hz, 2H), 3.53-3.44 (m, 3H), 3.35
(m, 1H), 3.22 (d, J=9.2 Hz, 1H), 2.10 (m, 1H), 1.95 (m, 1H)
Example 150
3-phenyl-5-(pyrimidin-5-yl)-1H-pyrazolo[3,4-c]pyridine 150
[0228] Following the procedures in Example 136,
pyrimidin-5-ylboronic acid and
5-bromo-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyrid-
ine were reacted and the product was deprotected to give 150 as a
yellow solid (25 mg, 25%) over two steps. .sup.1H NMR (400 MHz,
DMSO) .delta. 9.59 (s, 1H), 9.26 (s, 1H), 9.21 (s, 1H), 8.79 (s,
1H), 8.40 (s, 1H), 8.18 (d, 2H), 7.57 (t, 2H), 7.47 (t, 1H). ESI MS
m/z=274 (M+1)
Example 156
3-(1H-pyrazol-4-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine
156
Step 1:
3-(1-Benzyl-1H-pyrazol-4-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyr-
an-2-yl)-1H-pyrazolo[3,4-c]pyridine
##STR00462##
[0230] Following the Suzuki coupling procedure of Example 159,
5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine
and
1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
were reacted and the product was consequently reacted by the Suzuki
coupling procedure of Example 10 with 3-pyridineboronic acid
pinacol ester. The product was purified via silica gel
chromatography using a gradient of methanol in DCM to afford 236 mg
(54%) of
3-(1-Benzyl-1H-pyrazol-4-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl-
)-1H-pyrazolo[3,4-c]pyridine over two steps. ESI MS m/z 437.1
(M+1).
Step 2:
3-(1H-Pyrazol-4-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)--
1H-pyrazolo[3,4-c]pyridine
##STR00463##
[0232] A mixture of 234 mg (0.54 mmol) of
3-(1-benzyl-1H-pyrazol-4-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl-
)-1H-pyrazolo[3,4-c]pyridine, 3.0 ml (32 mmol) of
1,4-cyclohexadiene and 400 mg of 20% palladium hydroxide on carbon
was heated to reflux for 8 hours. The mixture was filtered, the
filtrate concentrated in vacuum to afford 106 mg (31%) of
3-(1H-Pyrazol-4-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyra-
zolo[3,4-c]pyridine over three steps. ESI MS m/z 347.1 (M+1).
Step 3
[0233] Following the deprotection of
3-(1H-Pyrazol-4-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyra-
zolo[3,4-c]pyridine by the procedure of Example 229, the product
was purified by triturating with ethyl ether and collected by
filtration to afford 24 mg (7%) of 156 over four steps. ESI MS m/z
263.0 (M+1). 1H NMR (400 MHz, DMSO): 9.70 (s, 1H), 9.37 (d, J=8.3
Hz, 1H), 9.22 (s, 1H), 8.94-8.84 (m, 2H), 8.48 (s, 2H), 8.19-8.11
(m, 1H)
Example 158
1-(5-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-3-yl)piperid-
in-4-amine 158
Step 1: tert-butyl
1-(5-bromopyridin-3-yl)piperidin-4-ylcarbamate
##STR00464##
[0235] A solution of 3,5-dibromopyridine (0.400 g, 1.69 mmol),
4-(N-Boc-amino)-piperidine (0.238 g, 1.19 mmol),
Tris(dibenzylideneacetone)dipalladium(0) (54 mg, 0.059 mmol),
rac-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl (73.9 mg, 0.119
mmol), and Sodium-tert-butoxide (114 mg, 1.19 mmol) in Toluene
(16.9 mL) was heated at 85.degree. C. for 18 h. The reaction was
filtered thru celite then rinsed with EtOAc. The crude product was
purified by Isco (EtOAc/Hep eluted at 40%) to give tert-butyl
1-(5-bromopyridin-3-yl)piperidin-4-ylcarbamate (320 mg, 75.6%
yield). ESI MS m/z=357.1 (M+1).
Step 2: tert-butyl
1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)piperidin--
4-ylcarbamate
##STR00465##
[0237] A solution of tert-butyl
1-(5-bromopyridin-3-yl)piperidin-4-ylcarbamate (0.120 g, 0.337
mmol), Bispinacol ester boronate (0.13 g, 0.50 mmol),
1,1'-Bis(diphenylphosphino)ferrocenepalladium (11) chloride (13.75
mg, 0.01684 mmol) and Potassium acetate (99.17 mg, 1.010 mmol) in
1,4-Dioxane (5.00 mL) was purged N2 then heat at 85.degree. C. 18
h. The reaction mixture was filtered thru celite and washed with
EtOAc. The filtrate was washed water and brine. The organic layer
was dried with Na2 SO4 and concentrated. The crude tert-butyl
1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)piperidin--
4-ylcarbamate was carried to next step. ESI MS m/z=404.1 (M+1).
Step 3: tert-butyl
1-(5-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl-
)pyridin-3-yl)piperidin-4-ylcarbamate
##STR00466##
[0239]
5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyrid-
ine (0.0736 g, 0.180 mmol), tert-butyl
1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)piperidin--
4-ylcarbamate (0.080 g, 0.20 mmol) and
1,1'-Bis(diphenylphosphino)ferrocenepalladium (II) chloride (0.0221
g, 0.0270 mmol) were dissolved in Acetonitrile (3.00 mL), followed
by the addition of 1.0 M of Potassium acetate in Water (0.270 mL)
and 1.0 M of Sodium carbonate in Water (0.270 mL). The reaction was
stirred at 80.degree. C. for 1 h. After filtration, the crude was
evaporated and purified by silica gel column using (EtOAc/Hep
eluted at 75% EtOAc) to give tert-butyl
1-(5-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl-
)pyridin-3-yl)piperidin-4-ylcarbamate (45 mg, 45% yield). ESI MS
m/z=558.1 (M+1).
Step 4: tert-butyl
1-(5-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyr-
idin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate
##STR00467##
[0241] To a mixture of tert-butyl
1-(5-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl-
)pyridin-3-yl)piperidin-4-ylcarbamate (45.0 mg, 0.0807 mmol),
3-Pyridylboronic acid (29.8 mg, 0.242 mmol) and
1,1'-Bis(diphenylphosphino)ferrocenepalladium (II) chloride (9.888
mg, 0.01211 mmol) in Acetonitrile (1.01 mL, 19.4 mmol) was added
1.0 M of Potassium acetate in Water (0.121 mL) and 1.0 M of Sodium
carbonate in Water (0.121 mL). The reaction mixture was irradiated
in microwave at 125.degree. C. for 20 min. The reaction was
filtered thru celite. The filtrate was washed H2O and brine. The
organic layer was dried with Na2SO4, filtered, and concentrated to
give tert-butyl
1-(5-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyr-
idin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate.
Step 5
[0242] To a solution of tert-butyl
1-(5-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyr-
idin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate in methylene
chloride (1.00 mL, 15.6 mmol) was added trifluoroacetic Acid
(0.3109 mL, 4.036 mmol). The reaction was stirred at RT for 18
hours. The reaction was concentrated then submitted for rHPLC
(reverse phase HPLC) to give 158 (10 mg, 33% yield). ESI MS
m/z=372.1 (M+1). .sup.1H NMR (400 MHz, DMSO) .delta. 9.39 (s, 1H),
9.24 (s, 1H), 8.72 (s, 1H), 8.61-8.52 (m, 3H), 8.42 (s, 1H), 7.83
(s, 1H), 7.55-7.48 (m, 1H), 3.85 (d, J=13.0 Hz, 2H), 2.98-2.76 (m,
3H), 1.91-1.81 (m, 2H), 1.42 (dd, J=20.7, 10.2 Hz, 2H)
Example 159
N1-(4-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)ethane-
-1,2-diamine 159
Step 1:
5-(3,4-Dihydro-2H-pyran-5-yl)-3-(6-fluoropyridin-2-yl)-1-(tetrahyd-
ro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine
##STR00468##
[0244] Following the Suzuki coupling procedure of Example 10,
5-bromo-3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo-
[3,4-c]pyridine and
2-(3,4-dihydro-2H-pyran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
were reacted and purified via silica gel chromatography using a
gradient of EtOAc in heptane to afford 68 mg (45%) of
5-(3,4-Dihydro-2H-pyran-5-yl)-3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-p-
yran-2-yl)-1H-pyrazolo[3,4-c]pyridine. ESI MS m/z 381.1 (M+1).
Step 2:
3-(6-Fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-5-(tetrahydr-
o-2H-pyran-3-yl)-1H-pyrazolo[3,4-c]pyridine
##STR00469##
[0246] A mixture of 68 mg (0.18 mmol) of
5-(3,4-dihydro-2H-pyran-5-yl)-3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-p-
yran-2-yl)-1H-pyrazolo[3,4-c]pyridine, 2.0 ml (21 mmol) of
1,4-cyclohexadiene and 300 mg of 10% palladium on carbon in 8 ml of
ethanol was heated to reflux for 24 hours. The mixture was filtered
through celite, the filtrate concentrated in vacuum to afford 70 mg
(100%) of
3-(6-Fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-5-(tetrah-
ydro-2H-pyran-3-yl)-1H-pyrazolo[3,4-c]pyridine. ESI MS m/z 383.1
(M+1).
Step 3:
3-(6-(Piperazin-1-yl)pyridin-2-yl)-5-(tetrahydro-2H-pyran-3-yl)-1H-
-pyrazolo[3,4-c]pyridine
##STR00470##
[0248] Following the procedure of Example 144,
3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-5-(tetrahydro-2H-py-
ran-3-yl)-1H-pyrazolo[3,4-c]pyridine and piperazine were reacted
and consequently deprotected by the procedure of Example 131, to
give a racemic mixture purified via reverse phase HPLC using a
gradient of MeOH in water with 0.1% NH.sub.4OH to afford 30 mg
(20%) of
3-(6-(Piperazin-1-yl)pyridin-2-yl)-5-(tetrahydro-2H-pyran-3-yl)-1H-pyrazo-
lo[3,4-c]pyridine. ESI MS m/z 365.1 (M+1).
Step 4:
3-(2-Fluoropyridin-4-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-
-yl)-1H-pyrazolo[3,4-c]pyridine
##STR00471##
[0250] A mixture of 0.408 g (1.00 mmol) of
5-bromo-3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo-
[3,4-c]pyridine, 0.162 g, (1.15 mmol) of 3-pyridineboronic acid
pinacol ester and 0.817 g (0.10 mmol) of
1,1'bis(diphenylphosphino)ferrocenepalladium (II) chloride and 1.2
ml of 1.0 M of Cesium Carbonate in water in 12 ml of acetonitrile
was degassed and heated in a sealed glass vial at 95.degree. C. for
2 hours. The mixture was filtered and the filtrate concentrated in
vacuum. The residue was dissolved in dichloromethane, the organic
layer washed with water, brine, dried over MgSO4 and concentrated
to give
3-(2-Fluoropyridin-4-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-
-pyrazolo[3,4-c]pyridine.
Step 5
[0251] Following the procedure of Example 143,
3-(2-fluoropyridin-4-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-
-pyrazolo[3,4-c]pyridine and 1,2-ethylenediamine were reacted and
purified via reverse phase HPLC using a gradient of MeOH in water
with 0.1% NH.sub.4OH to afford 32 mg (64%) of 159. ESI MS m/z 332.1
(M+1). 1H NMR (400 MHz, DMSO): 9.38 (s, 1H), 9.23 (s, 1H), 8.60 (d,
J=11.0 Hz, 2H), 8.53 (d, J=7.1 Hz, 1H), 8.10 (s, 1H), 7.54 (s, 1H),
7.25 (d, J=11.9 Hz, 2H), 6.67 (s, 1H), 2.78 (s, 2H)
Example 160
(S)-1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pip-
eridin-3-amine 160
[0252] Following the procedure of Example 144,
3-(2-fluoropyridin-4-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-
-pyrazolo[3,4-c]pyridine and tert-butyl piperidin-4-ylcarbamate
were reacted and consequently deprotected by the procedure of
Example 229, the mixture was purified via reverse phase HPLC using
a gradient of MeOH in water with 0.1% NH.sub.4OH to afford 50 mg
(59%) of 160. ESI MS m/z 372.1 (M+1)
Example 161
(S)-1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pip-
eridin-3-amine 161
[0253] Following the procedures of Example 144,
3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-
-pyrazolo[3,4-c]pyridine and (R)-benzyl piperidin-3-ylcarbamate
were reacted. The reaction mixture was purified via reverse phase
HPLC using a gradient of MeOH in water with 0.1% NH.sub.4OH to
afford 20.0 mg (20%) of 161 over two steps. ESI MS m/z 372.1 (M+1).
1H NMR (400 MHz, DMSO): 9.30 (s, 1H), 9.21 (s, 1H), 9.00 (s, 1H),
8.60 (s, 1H), 8.48 (m, 1H), 7.66 (s, 1H) 7.53 (m, 1H), 7.46 (s,
1H), 6.87 (d, J=8.5 Hz, 1H), 4.37 (m, 1H), 4.29 (d, J=12.6 Hz, 1H),
3.06-2.97 (m, 1H), 2.79 (d, J=7.6 Hz, 2H), 1.94 (m, 1H), 1.80 (m,
1H), 1.61 (d, J=9.5 Hz, 1H), 1.34 (m, 1H)
Example 162
3-(6-(piperazin-1-yl)pyridin-2-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyri-
dine 162
[0254] Following the procedures of Example 143,
3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-
-pyrazolo[3,4-c]pyridine and piperazine were reacted and purified
via reverse phase HPLC using a gradient of MeOH in water with 0.1%
NH.sub.4OH to afford 42 mg (78%) of 162. ESI MS m/z 358.1 (M+1). 1H
NMR (400 MHz, DMSO): 9.24 (d, J=8.1 Hz, 1H), 8.90 (s, 1H), 8.61 (s,
1H), 8.42 (d, J=7.2 Hz, 1H), 7.74 (d, J=7.9 Hz, 1H), 7.56 (d, J=6.7
Hz, 1H), 6.96 (d, J=8.1 Hz, 1H), 3.82 (s, 2H), 3.17 (s, 2H)
Example 163
3,5-bis(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine
163
[0255]
3,5-bis(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-p-
yrazolo[3,4-c]pyridine in methanol was treated with 4M HCl in
1,4-dioxane at 50.degree. C. for 3 h. Volatile solvent was
evaporated in vacuo. The resultant residue was purified by reverse
phase HPLC to give 163 as a white solid (34.2%). .sup.1H NMR (500
MHz, DMSO) .delta. 13.35 (s, 1H), 8.96 (s, 1H), 8.47 (s, 1H), 8.29
(s, 1H), 8.15 (s, 1H), 8.10 (d, J=5.6 Hz, 2H), 3.96 (s, 3H), 3.90
(s, 3H). LC/MS: m/z 280.0 [M+1]
Example 165
(1-(5-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-3-yl)piperi-
din-4-yl)methanamine 165
[0256] Following the procedures in Example 158, tert-butyl
(1-(5-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-y-
l)pyridin-3-yl)piperidin-4-yl)methylcarbamate was converted to 165.
ESI MS m/z=386.1 (M+1). .sup.1H NMR (400 MHz, DMSO) .delta. 9.37
(s, 1H), 9.23 (s, 1H), 8.59 (d, J=4.6 Hz, 1H), 8.55 (s, 1H), 8.52
(s, 1H), 8.06 (d, J=2.4 Hz, 1H), 7.56 (s, 1H), 7.51 (dd, J=8.0, 4.7
Hz, 1H), 6.13 (d, J=5.3 Hz, 1H), 3.15-3.00 (m, 4H), 2.62 (dd,
J=25.8, 13.5 Hz, 2H), 1.90-1.76 (m, 3H), 1.21 (dd, J=10.6 Hz,
2H)
Example 168
(R)-(1-(5-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-3-yl)py-
rrolidin-3-yl)methanamine 168
[0257] Following the procedures in Example 158, tert-butyl
((3R)-1-(5-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridi-
n-3-yl)pyridin-3-yl)pyrrolidin-3-yl)methylcarbamate was converted
to 168. ESI MS m/z=372.1 (M+1). .sup.1H NMR (400 MHz, DMSO) .delta.
9.39 (d, J=1.7 Hz, 1H), 9.24 (s, 1H), 8.70-8.52 (m, 4H), 8.03 (d,
J=2.6 Hz, 1H), 7.51 (dd, J=7.9, 4.8 Hz, 1H), 7.43 (s, 1H),
3.59-3.45 (m, 4H), 2.81 (d, J=7.1 Hz, 2H), 2.20-2.12 (m, 1H),
1.87-1.74 (m, 1H)
Example 169
1-(5-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-3-yl)azepan--
4-amine 169
[0258] Following the procedures in Example 158, tert-butyl
1-(5-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl-
)pyridin-3-yl)azepan-4-ylcarbamate was converted to 169. ESI MS
m/z=386.2 (M+1). .sup.1H NMR (400 MHz, DMSO) .delta. 9.38 (s, 1H),
9.24 (s, 1H), 8.64-8.49 (m, 4H), 8.21 (d, J=2.7 Hz, 1H), 7.58 (s,
1H), 7.51 (dd, J=7.8, 4.8 Hz, 1H), 3.76-3.65 (m, 1H), 3.66-3.57 (m,
1H), 3.56-3.43 (m, 2H), 3.04 (dd, J=14.6, 9.5 Hz, 1H), 2.12-2.00
(m, 1H), 2.01-1.90 (m 1H), 1.83-1.59 (m, 2H), 1.53-1.37 (m, 1H),
1.25-1.15 (m, 1H)
Example 170
N-(piperidin-4-yl)-5-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyri-
din-3-amine 170
[0259] Following the procedures in Example 158, tert-butyl
4-(5-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl-
)pyridin-3-ylamino)piperidine-1-carboxylate was converted to 170.
ESI MS m/z=372.1 (M+1). .sup.1H NMR (400 MHz, DMSO) .delta. 9.37
(d, J=2.0 Hz, 1H), 9.23 (s, 1H), 8.59 (d, 0.1=4.6 Hz, 1H),
8.56-8.47 (m, 3H), 8.05 (d, 0.1=2.4 Hz, 1H), 7.57 (s, 1H), 7.51
(dd, J=7.9, 4.7 Hz, 1H), 5.90 (d, J=8.0 Hz, 1H), 2.99 (d, J=12.5
Hz, 2H), 2.60 (t, J=11.0 Hz, 2H), 1.95 (d, J=10.6 Hz, 2H), 1.30
(dd, J=19.6, 10.8 Hz, 2H)
Example 172
3-(2-fluoro-5-methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4--
c]pyridine 172
Step 1:
3-(2-fluoro-5-methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetra-
hydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine
##STR00472##
[0261] In a microwave vial was charged with
3-chloro-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyr-
azolo[3,4-c]pyridine (29.4 mg, 0.093 mmol),
2-(2-fluoro-5-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
(35.0 mg, 0.139 mmol), potassium acetate (13.6 mg, 0.14 mmol),
sodium carbonate (14.7 mg, 0.14 mmol), and
bis(diphenylphosphino)ferrocene]dichloropalladium (II), complexed
with dichloromethane (1:1) (7.5 mg, 9.2E.sup.-3 mmol). Degassed
acetonitrile (0.8 mL) and water (0.3 mL) were added. Nitrogen was
passed through the mixture for 15 minutes and the vial was capped.
The reaction mixture was subjected to microwave irradiation at
125.degree. C. for 25 min. The reaction mixture was filtered
through a pad of Celite.RTM. and diluted with water and EtOAc. The
organic layer was washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated under reduced pressure. The crude
product was purified using flash chromatography (Si-PPC gradient
elution, solvent: 10-100% ethyl acetate in heptanes) to give
3-(2-fluoro-5-methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2-
H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine as a foam (37.3 mg,
98.9%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.12 (s, 1H),
7.95 (s, 1H), 7.90 (s, 1H), 7.81 (d, J=2.8 Hz, 1H), 7.32 (dd,
J=5.5, 3.2 Hz, 1H), 7.15 (t, J=9.4 Hz, 1H), 6.97-6.89 (m, 1H), 5.86
(dd, J=8.7, 2.1 Hz, 1H), 4.07-3.98 (m, 1H), 3.93 (s, 3H), 3.86-3.74
(m, 4H), 2.64-2.47 (m, 1H), 2.16 (d, J=9.7 Hz, 2H), 1.83-1.66 (m,
3H). LC/MS: m/z 408.2 [M+1].
Step 2
[0262] To a stirred mixture of
3-(2-fluoro-5-methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2-
H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (37.0 mg, 0.09 mmol) in
methanol (5.0 mL) was added 6 M HCl in water (0.66 mL). The
reaction mixture was stirred at 60.degree. C. for 3 days. Volatile
solvent was evaporated in vacuo, and the crude was diluted into
ethyl acetate (.about.30 mL). The organic layer was washed with
saturated aqueous sodium bicarbonate solution, water and brine,
dried over Na.sub.2SO.sub.4, filtered, and concentrated under
reduced pressure. Trituration from ether-heptanes afforded 172 as a
solid (15.3 mg, 52.1%). .sup.1H NMR (400 MHz, DMSO) .delta. 13.88
(s, 1H), 9.06 (s, 1H), 8.25 (s, 1H), 7.97 (s, 1H), 7.88 (s, 1H),
7.36 (t, J=9.6 Hz, 1H), 7.31 (dd, J=5.7, 3.2 Hz, 1H), 7.09 (s, 1H),
3.88 (s, 3H), 3.83 (s, 3H). LC/MS: m/z 324.0 [M+1]
Example 173
(S)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyri-
din-2-yl)piperidin-3-amine 173
[0263] Following the procedures as described in Example 189,
3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-py-
ran-2-yl)-1H-pyrazolo[3,4-c]pyridine and (S)-tert-butyl
piperidin-3-ylcarbamate were reacted and the product was
deprotected to give 173 as a white solid (71.7% over two steps).
.sup.1H NMR (400 MHz, DMSO) .delta. 1H NMR (400 MHz, DMSO) .delta.
9.03 (d, J=1.2 Hz, 1H), 8.59 (d, J=1.2 Hz, 1H), 8.34 (s, 1H), 7.95
(s, 1H), 7.67-7.60 (m, 1H), 7.42 (d, J=7.3 Hz, 1H), 6.84 (d, J=8.5
Hz, 1H), 4.46 (d, J=8.9 Hz, 1H), 4.21 (d, J=12.7 Hz, 1H), 3.90 (s,
3H), 3.02-2.93 (m, 1H), 2.84-2.74 (m, 2H), 2.00-1.92 (m, 2H),
1.88-1.77 (m, 2H), 1.67-1.52 (m, 2H), 1.39-1.28 (m, 1H). LC/MS: m/z
375.1 [M+1]
Example 174
1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin--
2-yl)piperidin-4-amine 174
[0264] Following the procedures as described in Example 189,
3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-py-
ran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl
piperidin-4-ylcarbamate were reacted and the product was
deprotected to give 174 as a white solid (36.8% over two steps).
.sup.1H NMR (400 MHz, DMSO) .delta. 1H NMR (400 MHz, DMSO) .delta.
9.03 (d, J=1.2 Hz, 1H), 8.54 (d, J=1.3 Hz, 1H), 8.12 (s, 1H), 7.82
(s, 1H), 7.63 (dd, J=8.4, 7.5 Hz, 1H), 7.41 (d, J=7.3 Hz, 1H), 6.86
(d, J=8.5 Hz, 1H), 4.37 (d, J=13.1 Hz, 2H), 3.91 (s, 3H), 3.51-3.20
(m, 3H), 3.14-3.04 (m, 2H), 2.96-2.83 (m, 1H), 1.87 (d, J=9.9 Hz,
2H), 1.45-1.27 (m, 2H). LC/MS: m/z 375.1 [M+1]
Example 175
3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]-
pyridine 175
Step 1: tert-Butyl
4-(4-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyr-
idin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate
##STR00473##
[0266] Following the Suzuki coupling procedure of Example 159,
5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine
and tert-butyl
4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperi-
dine-1-carboxylate were reacted and the product was consequently
reacted by the Suzuki coupling procedure of Example 10 with
3-pyridineboronic acid pinacol ester. The product mixture was
purified via silica gel chromatography using a gradient of methanol
in DCM to afford 230 mg (75%) of tert-Butyl
4-(4-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyr-
idin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate over two steps.
ESI MS m/z 530.2 (M+1).
Step 2
[0267] Deprotection following the procedure of Example 229, of
tert-Butyl
4-(4-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyr-
idin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and
purification via reverse phase HPLC using a gradient of MeOH in
water with 0.1% NH.sub.4OH gave 42 mg (21%) of 175. ESI MS m/z
346.1 (M+1). 1H NMR (400 MHz, DMSO): 13.75 (s, 1H), 9.44 (d, J=1.7
Hz, 1H), 9.15 (d, J=1.2 Hz, 1H), 8.64 (s, 1H), 8.61-8.56 (m, 3H),
4.36-4.26 (m, 1H), 3.09 (d, J=12.3 Hz, 2H), 2.68-2.57 (m, 2H),
2.05-1.87 (m, 4H)
Example 176
3,5-di(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine 176
[0268] To a microwave tube was added
5-bromo-3-iodo-1H-pyrazolo[3,4-c]pyridine (100 mg, 0.31 mmol),
pyridin-3-ylboronic acid (343 mg, 2.79 mmol), Pd(dppf) Cl.sub.2 (24
mg, 0.03 mmol), sodium carbonate (131 mg, 1.24 mmol),
1,2-dimethoxyethane (2 mL), ethanol (0.5 mL) and water (0.5 mL).
The tube was flushed with nitrogen for 2 minutes and heated in a
Biotage microwave at 160.degree. C. for 1 hour. The solvent was
distilled off and the crude product was purified via reverse phase
HPLC eluting with 15% CH.sub.3CN in aqueous 10 mmol
NH.sub.4HCO.sub.3 to afford 176 as a pale yellow solid (30 mg,
28%). .sup.1H NMR (500 MHz, DMSO).sup.1H NMR (500 MHz, DMSO)
.delta. 14.1 (s, 1H), 9.44 (s, 1H), 9.37 (s, 3H), 9.26 (s, 1H),
8.71 (s, 1H), 8.67-8.66 (m, 1H), 8.60-8.59 (m, 2H), 8.56-8.54 (m,
1H), 7.60-7.58 (m, 1H), 7.52-7.51 (m, 1H). ESI MS m/z=274 (M+1)
Example 177
(R)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyri-
din-2-yl)piperidin-3-amine 177
[0269] Following the procedures as described in Example 189,
3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-py-
ran-2-yl)-1H-pyrazolo[3,4-c]pyridine and (R)-tert-butyl
piperidin-3-ylcarbamate were reacted and the product was
deprotected to give 177 as a white solid (59.5% over two steps).
.sup.1H NMR (400 MHz, DMSO) .delta. 9.03 (d, J=1.1 Hz, 1H), 8.60
(s, 1H), 8.34 (s, 1H), 7.95 (s, 1H), 7.69-7.56 (m, 1H), 7.42 (d,
J=7.3 Hz, 1H), 6.83 (d, J=8.6 Hz, 1H), 4.47 (d, J=9.0 Hz, 1H), 4.22
(d, J=12.8 Hz, 1H), 3.89 (s, 3H), 3.04-2.90 (m, 1H), 2.81-2.66 (m,
2H), 2.01-1.92 (m, 2H), 1.88-1.74 (m, 2H), 1.56-1.52 (m, 2H),
1.37-1.27 (m, 1H). LC/MS: m/z 375.1 [M+1].
Example 178
2-(4-(3-(6-fluoropyridin-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1H-pyrazol--
1-yl)acetamide 178
Step 1: Ethyl
2-(4-(3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3-
,4-c]pyridin-5-yl)-1H-pyrazol-1-yl)acetate
##STR00474##
[0271] Following the Suzuki coupling procedure of Example 10,
5-bromo-3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo-
[3,4-c]pyridine and ethyl
2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetat-
e, were reacted and purified via silica gel chromatography using a
gradient of EtOAc in heptane to afford 100 mg (56%) of Ethyl
2-(4-(3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3-
,4-c]pyridin-5-yl)-1H-pyrazol-1-yl)acetate. ESI MS m/z 451.1
(M+1).
Step 2:
2-(4-(3-(6-Fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyr-
azolo[3,4-c]pyridin-5-yl)-1H-pyrazol-1-yl)acetic acid
##STR00475##
[0273] A mixture of 100 mg (0.22 mmol) of ethyl
2-(4-(3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3-
,4-c]pyridin-5-yl)-1H-pyrazol-1-yl)acetate and 1 ml of 1 M aqueous
solution of lithium hydroxide in 6 ml of methanol and 2 ml of
tetrahydrofuran was stirred for 2 hours. The mixture was
concentrated in vacuum and neutralized to pH 5 by careful addition
of 1 N aqueous HCl. The product was collected by filtration, washed
with water and dried in high vacuum to afford 82 mg (85%) of
2-(4-(3-(6-Fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3-
,4-c]pyridin-5-yl)-1H-pyrazol-1-yl)acetic acid. ESI MS m/z 423.0
(M+1).
Step 3:
2-(4-(3-(6-Fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyr-
azolo[3,4-c]pyridin-5-yl)-1H-pyrazol-1-yl)acetamide
##STR00476##
[0275] Following the procedure of Example 144,
2-(4-(3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3-
,4-c]pyridin-5-yl)-1H-pyrazol-1-yl)acetic acid and ammonium
chloride were reacted to give 60 mg (75%) of
2-(4-(3-(6-Fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3-
,4-c]pyridin-5-yl)-1H-pyrazol-1-yl)acetamide. ESI MS m/z 422.2
(M+1).
Step 4
[0276] A mixture of 60 mg (0.142 mmol) of
2-(4-(3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3-
,4-c]pyridin-5-yl)-1H-pyrazol-1-yl)acetamide and 2 ml of
trifluoroacetic acid was stirred for 18 hours. The mixture was
concentrated in vacuum, the residue stirred with 5 ml of saturated
aqueous sodium bicarbonate for 30 min. The precipitate was
collected by filtration, washed with water and recrystallized from
methanol affording 35 mg (26%) of 178 over 4 steps. ESI MS m/z
338.0 (M+1). 1H NMR (400 MHz, DMSO): 14.02 (s, 1H), 9.10 (s, 1H),
8.46 (s, 1H), 8.28 (s, 1H), 8.17-8.09 (m, 2H), 7.99 (s, 1H), 7.51
(s, 1H), 7.28 (s, 1H), 7.20 (dt, J=5.4, 2.7 Hz, 1H), 4.84 (s,
2H)
Example 182
(1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-
-2-yl)piperidin-4-yl)methanamine 182
[0277] Following the procedures as described in Example 189,
3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-py-
ran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl
piperidin-4-ylmethylcarbamate were reacted and the product was
deprotected to give 182 as a white solid (63% over two steps).
.sup.1H NMR (400 MHz, DMSO) .delta. 9.03 (s, 1H), 8.54 (s, 1H),
8.11 (s, 1H), 7.82 (s, 1H), 7.63 (t, J=8.0 Hz, 1H), 7.41 (d, J=7.4
Hz, 1H), 6.84 (d, J=8.5 Hz, 1H), 4.50 (d, J=12.1 Hz, 2H), 3.91 (s,
3H), 2.99 (t, J=12.5 Hz, 2H), 2.53-2.44 (m, 4H), 1.92-1.74 (m, 3H),
1.58 (s, 1H), 1.31-1.18 (m, 2H). LC/MS: m/z 389.2 [M+1]
Example 183
6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-(piperid-
in-4-ylmethyl)pyridin-2-amine 183
[0278] Following the procedures as described in Example 189,
3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-py-
ran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl
4-(aminomethyl)piperidine-1-carboxylate were reacted and the
product was deprotected to give 183 as a white solid (55% over two
steps). .sup.1H NMR (400 MHz, DMSO) .delta. 9.01 (s, 1H), 8.66 (s,
1H), 8.16 (s, 1H), 7.92 (s, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.30 (d,
J=7.3 Hz, 1H), 6.76-6.70 (m, 1H), 6.50 (d, J=8.3 Hz, 1H), 3.90 (s,
3H), 3.44-3.34 (m, 4H), 2.99 (d, J=12.2 Hz, 2H), 2.55-2.44 (m, 2H),
1.85-1.71 (m, 3H), 1.27-1.09 (m, 2H). LC/MS: m/z 389.2 [M+1]
Example 184
5-(1-methyl-1H-pyrazol-4-yl)-3-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)--
1H-pyrazolo[3,4-c]pyridine 184
[0279] Following the procedure in Example 189,
5-(1-methyl-1H-pyrazol-4-yl)-3-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-
-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine was
deprotected to give 184 as a solid (52.1%). .sup.1H NMR (400 MHz,
DMSO) .delta. 13.85 (s, 1H), 9.08 (s, 1H), 8.66 (s, 1H), 8.43 (s,
1H), 8.25 (s, 1H), 8.16 (s, 1H), 7.98 (d, J=7.5 Hz, 2H), 7.90 (t,
J=7.8 Hz, 1H), 7.65 (d, J=7.7 Hz, 1H), 3.98 (s, 3H), 3.93 (s, 3H).
LC/MS: m/z 357.1 [M+1]
Example 185
5-(furan-3-yl)-3-phenyl-1H-pyrazolo[3,4-c]pyridine 185
[0280] Following the procedures as described in Example 176,
pyrimidin-5-ylboronic acid and
5-bromo-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine
were reacted and the product was deprotected to give 185 as a white
solid (25 mg, 28%) over two step. .sup.1H NMR (400 MHz, DMSO)
.delta. 9.00 (s, 1H), 8.17 (t, 1H), 8.14 (t, 1H), 8.03 (t, 2H),
7.06-7.60 (m, 3H), 7.45 (t, 1H), 7.05 (s, 1H). ESI MS m/z=262
(M+1)
Example 186
3-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-5-(pyridin-3-yl)-1H-pyrazolo[-
3,4-c]pyridine 186
Step 1: tert-Butyl
4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methy-
l)piperidine-1-carboxylate
##STR00477##
[0282] A solution of 630.8 mg (2.5 mmol) of
1,1'-(azodicarbonyl)-dipiperidine in 5 ml of THF was added dropwise
to a mixture of 388 mg (2.0 mmol) of
4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane, 538 mg
(2.5 mmol) of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate
and 0.62 ml (2.5 mmol) of tributylphosphine in 6 ml of
tetrahydrofuran at 0.degree. C. The mixture was stirred for 18
hours. The precipitate was filtered out and washed with ethyl
ether. The filtrate was mixed with 50 ml of water and extracted
with ethyl ether. The organic layer was washed with water, brine,
dried over MgSO4 and concentrated. The residue was purified on 24 g
silica column eluting with MeOH 0-4% gradient in DCM to afford 0.43
g (55%) of tert-Butyl
4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methy-
l)piperidine-1-carboxylate. ESI MS m/z 392.1
Step 2
[0283] Following the Suzuki coupling procedure of Example 159,
5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine
and tert-butyl
4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperi-
dine-1-carboxylate were reacted. The product was subsequently
reacted with 3-pyridineboronic acid pinacol ester by the Suzuki
coupling procedure of Example 10 and deprotected by the procedure
of Example 229. The mixture was purified via reverse phase HPLC
using a gradient of MeOH in water with 0.1% NH.sub.4OH to afford 25
mg (14%) of 186 over three steps. ESI MS m/z 360.1 (M+1). 1H NMR
(400 MHz, DMSO) 9.44 (d, J=2.1 Hz, 1H), 9.15 (d, J=1.0 Hz, 1H),
8.64-8.54 (m, 4H), 8.17 (s, 1H), 7.53 (dd, J=8.0, 4.8 Hz, 1H), 4.08
(d, J=7.2 Hz, 2H), 2.91 (d, J=12.0 Hz, 2H), 2.41 (t, J=10.9 Hz,
2H), 1.98 (s, 1H), 1.45 (d, J=11.2 Hz, 2H), 1.18-1.05 (m, 2H)
Example 187
3-(6-(1,4-diazepan-1-yl)pyridin-2-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]p-
yridine 187
[0284] Following the procedures of Example 143 and starting with
3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-
-pyrazolo[3,4-c]pyridine and homopiperazine, 187 was obtained and
lyophilized from water to afford 42 mg (78%). ESI MS m/z 372.1
(M+1). 1H NMR (400 MHz, DMSO)9.58 (s, 1H), 9.44 (s, 1H), 9.36 (s,
2H), 9.31 (s, 1H), 9.11 (d, J=8.3 Hz, 1H), 8.99 (s, 1H), 8.94 (d,
J=5.4 Hz, 1H), 8.23-8.15 (m, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.52 (d,
J=7.4 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 4.12 (s, 2H), 3.89 (t, J=6.0
Hz, 2H), 3.43 (d, J=21.5 Hz, 2H), 3.27-3.17 (m, 2H), 2.24 (s,
2H)
Example 188
1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin--
2-yl)azepan-4-amine 188
[0285] Following the procedures as described in Example 189,
3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-py-
ran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl
azepan-4-ylcarbamate were reacted. The product was deprotected to
give 188 as a white solid (47.1% over two steps). .sup.1H NMR (400
MHz, DMSO) .delta. 9.02 (s, 1H), 8.55 (s, 1H), 8.11 (s, 1H), 7.83
(s, 1H), 7.60 (t, J=8.0 Hz, 1H), 7.37 (d, J=7.3 Hz, 1H), 6.61 (d,
J=8.5 Hz, 1H), 4.02-3.86 (m, 4H), 3.85-3.75 (m, 1H), 3.75-3.55 (m,
3H), 2.93-2.85 (s, 1H), 2.10-1.93 (m, 2H), 1.89-1.56 (m, 3H),
1.45-1.31 (m, 1H); 2 protons not seen. LC/MS: m/z 389.2 [M+1]
Example 189
(R)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyri-
din-2-yl)pyrrolidin-3-amine 189
Step 1: tert-butyl
(3R)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-p-
yrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-ylcarbamate
##STR00478##
[0287] A mixture of
3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-py-
ran-2-yl)-1H-pyrazolo[3,4-c]pyridine (50.0 mg, 0.13 mmol) and
(R)-3-(Boc-amino)pyrrolidine (246.1 mg, 1.32 mmol) in DMSO (2.6 mL)
in a sealed tube was stirred at 95.degree. C. under N.sub.2 for 3
days. The cooled reaction mixture was diluted into 1:1 ether-ethyl
acetate. The organic layer was washed with 10% aqueous citric acid
until pH.about.4 to 5, water and brine, dried over
Na.sub.2SO.sub.4, filtered, and evaporated in vacuo. The crude
product was purified using flash chromatography (Si-PPC gradient
elution, solvent: 0-20% methanol in ethyl acetate) to give
tort-butyl
(3R)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-p-
yrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-ylcarbamate as
a foam (61.4 mg, 85.3%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
1H NMR (400 MHz, CDCl.sub.3) .delta. 9.11 (s, 1H), 8.79 (s, 1H),
8.05 (broad s, 1H), 7.97 (s, 1H), 7.62-7.50 (m, 2H), 6.37 (d, J=7.9
Hz, 1H), 5.86 (dd, J=8.5, 2.2 Hz, 1H), 4.79 (s, 1H), 4.44 (s, 1H),
4.07-3.95 (m, 4H), 3.92-3.84 (m, 1H), 3.84-3.69 (m, 3H), 3.63-3.51
(m, 1H), 2.64-2.49 (m, 1H), 2.37 (td, J=13.6, 7.7 Hz, 1H), 2.17 (d,
J=9.8 Hz, 2H), 2.11-2.01 (m, 1H), 1.89-1.68 (m, 3H), 1.46 (s, 9H).
LC/MS: m/z 545.3 [M+1].
Step 2: To a stirred solution of tert-butyl
(3R)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-p-
yrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-ylcarbamate
(60.0 mg, 0.12 mmol) in anhydrous DCM (5.0 mL) and methanol (2.5
mL) was added 4M HCl in 1,4-Dioxane (4.0 mL). The reaction mixture
was stirred at 60.degree. C. under N.sub.2 for 18 h. Volatile
solvent was evaporated in vacuo. The crude was redissolved in DMSO
(1 mL) and was purified by reverse phase HPLC to give 189 as a
white solid (25.5 mg, 58.4%). .sup.1H NMR (400 MHz, DMSO) .delta.
9.02 (s, 1H), 8.71 (s, 1H), 8.13 (s, 1H), 7.87 (s, 1H), 7.59 (t,
J=7.9 Hz, 1H), 7.36 (d, J=7.4 Hz, 1H), 6.41 (d, J=8.4 Hz, 1H), 3.91
(s, 3H), 3.81-3.64 (m, 4H), 3.63-3.52 (m, 2H), 2.17 (dt, J=12.3,
6.5 Hz, 2H), 1.88-1.75 (m, 2H). LC/MS: m/z 361.1 [M+1]
Example 191
(R)-1-(5-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pip-
eridin-3-amine 191
[0288] A solution containing
3-(6-fluoropyridin-3-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-
-pyrazolo[3,4-c]pyridine (0.070 g, 0.00019 mol) and (R)-tert-butyl
piperidin-3-ylcarbamate (0.224 g, 0.00112 mol) in Dimethyl
sulfoxide (1.40 mL, 0.0197 mol) was heated at 95.degree. C. for 18
h. The reaction was quenched with water then filtered and washed
with water. The crude product was dried under high vacuum overnight
to give tert-butyl
(3R)-1-(5-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4--
c]pyridin-3-yl)pyridin-2-yl)piperidin-3-ylcarbamate which was
dissolved in Methylene chloride (1.4 mL, 0.022 mol) and treated
with trifluoroacetic Acid (0.72 mL, 0.0093 mol). The reaction was
stirred at RT 18 h. The reaction was concentrated then submitted
for rHPLC to give 191 (50.6 mg, 73% yield). ESI MS m/z=372.1 (M+1).
.sup.1H NMR (400 MHz, DMSO) .delta. 9.40 (d, J=1.7 Hz, 1H), 9.18
(s, 1H), 8.88 (d, J=2.3 Hz, 1H), 8.60-8.53 (m, 3H), 8.21 (dd,
J=8.9, 2.4 Hz, 1H), 7.50 (dd, J=7.7, 5.1 Hz, 1H), 6.97 (d, J=9.0
Hz, 1H), 4.27 (dd, J=23.6, 12.1 Hz, 2H), 2.88 (dd, J=17.5, 7.2 Hz,
2H), 2.73-2.56 (m, 2H), 1.89 (d, J=12.0 Hz, 1H), 1.73 (d, J=13.5
Hz, 1H), 1.47 (dd, J=24.5, 12.1 Hz, 1H), 1.25 (ddd, J=16.2, 12.6,
4.0 Hz, 1H)
Example 193
3-(1H-pyrazol-3-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine
193
[0289] A mixture of
3-(1H-pyrazol-3-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyra-
zolo[3,4-c]pyridine (29.36 mg, 0.08476 mmol) in 4.0 M of Hydrogen
chloride in 1,4-Dioxane (5 mL) and 1,4-Dioxane (5 mL) was stirred
at room temperature overnight. The reaction mixture was
concentrated and the residue was purified by reverse phase HPLC to
afford 193 as an off-white solid (10.2 mg, 45.9%). 1H NMR (400 MHz,
DMSO) .delta. 13.71 (s, 1H), 13.14 (s, 1H), 9.23 (d, J=31.1 Hz,
2H), 8.72-8.55 (m, 2H), 8.43 (s, 1H), 7.91 (s, 1H), 7.53 (dd,
J=8.0, 4.8 Hz, 1H), 6.84 (s, 1H); ESI MS m/z=263.0 (M+1)
Example 194
5-(pyridin-3-yl)-3-(pyridin-4-yl)-1H-pyrazolo[3,4-c]pyridine
194
[0290] To a microwave tube was added
3-iodo-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine from Example 4
(100 mg, 0.31 mmol), pyridin-4-ylboronic acid (190 mg, 1.55 mmol),
Pd(dppf) Cl.sub.2 (50 mg, 0.06 mmol), sodium carbonate (131 mg,
1.24 mmol), 1,2-dimethoxyethane (2 mL), ethanol (0.3 mL) and water
(0.3 mL). The tube was flushed with nitrogen for 2 minutes and
heated in a Biotage microwave at 160.degree. C. for 1 hour. The
solvent was distilled off and the crude product was purified via
reverse phase HPLC eluting with 15% CH.sub.3CN aqueous 10 mmol
NH.sub.4HCO.sub.3 solution to afford 194 as a white solid (18 mg,
21%). .sup.1H NMR (400 MHz, DMSO) .sup.1H NMR (500 MHz, DMSO)
.delta. 9.44 (s, 1H), 9.28 (s, 1H), 8.76-8.73 (m, 3H), 8.62-8.59
(m, 2H), 8.19 (d, J=6.0 Hz, 2H), 7.55-7.53 (m, 1H). ESI MS m/z=274
(M+1)
Example 196
(S)-1-(5-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pip-
eridin-3-amine 196
[0291] Following the procedures in Example 191,
3-(6-fluoropyridin-3-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-
-pyrazolo[3,4-c]pyridine was converted to 196. ESI MS m/z=372.1
(M+1). .sup.1H NMR (400 MHz, DMSO) .delta. 9.40 (d, J=1.6 Hz, 1H),
9.18 (s, 1H), 8.87 (d, J=2.4 Hz, 1H), 8.62-8.50 (m, 3H), 8.21 (dd,
J=8.9, 2.4 Hz, 1H), 7.50 (dd, J=8.0, 4.7 Hz, 1H), 6.97 (d, J=9.0
Hz, 1H), 4.27 (dd, J=23.4, 12.0 Hz, 2H), 2.94-2.82 (m, 1H), 2.65
(m, 2H), 1.90 (d, J=9.1 Hz, 1H), 1.78-1.64 (m, 2H), 1.55-1.37 (m,
1H), 1.33-1.17 (m, 1H)
Example 197
1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan--
4-amine 197
[0292] Following the procedures in Example 191,
3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-
-pyrazolo[3,4-c]pyridine was converted to 197. ESI MS m/z=386.1
(M+1). .sup.1H NMR (400 MHz, DMSO) .delta. 9.25-9.17 (m, 1H), 8.97
(s, 1H), 8.60 (d, J=4.7 Hz, 1H), 8.38 (d, J=7.9 Hz, 1H), 7.66-7.59
(m, 1H), 7.55 (dd, J=7.9, 4.7 Hz, 1H), 7.42 (d, J=7.3 Hz, 1H), 6.64
(d, J=8.6 Hz, 1H), 3.99-3.89 (m, 1H), 3.86-1.77 (m, 1H), 3.74-3.56
(m, 1H), 2.98-2.83 (m, 1H), 2.08-1.96 (m, 2H), 1.92-1.54 (m, 3H),
1.47-1.34 (m, 1H)
Example 200
6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-N-(piperid-
in-4-yl)pyridin-2-amine 200
[0293] Following the procedures as described in Example 189,
3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-py-
ran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl
4-aminopiperidine-1-carboxylate were reacted and the product was
deprotected to give 200 as a white solid (5.4% over two steps).
.sup.1H NMR (400 MHz, MeOD) .delta. 8.97 (s, 1H), 8.61 (s, 1H),
8.47 (s, 2H), 8.12 (s, 1H), 8.01 (s, 1H), 7.55 (t, J=7.8 Hz, 1H),
7.44 (d, J=7.3 Hz, 1H), 6.57 (d, J=8.2 Hz, 1H), 4.69 (m, 1H),
4.41-4.32 (m, 1H), 3.99 (s, 3H), 3.52-3.43 (m, 2H), 3.12 (dd,
J=16.9, 6.7 Hz, 2H), 2.44-2.33 (m, 2H), 1.97-1.85 (m, 2H). LC/MS:
m/z 375.1 [M+1]
Example 202
(S)-1-(5-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pyr-
rolidin-3-amine 202
[0294] Following the procedures in Example 191,
3-(6-fluoropyridin-3-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-
-pyrazolo[3,4-c]pyridine was converted to 202. ESI MS m/z=358.1
(M+1). .sup.1H NMR (400 MHz, DMSO) .delta. 9.41 (s, 1H), 9.17 (s,
1H), 8.89 (d, J=2.2 Hz, 1H), 8.62-8.54 (m, 3H), 8.20 (dd, J=8.8,
2.3 Hz, 1H), 7.54-7.46 (m, 1H), 6.58 (d, J=8.8 Hz, 1H), 3.66-3.56
(m, 3H), 3.52-3.44 (m, 1H), 3.19-3.11 (m, 1H), 2.15-2.03 (m, 1H),
1.80-1.70 (m, 1H)
Example 203
(R)-1-(5-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pyr-
rolidin-3-amine 203
[0295] Following the procedures in Example 191,
3-(6-fluoropyridin-3-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-
-pyrazolo[3,4-c]pyridine was converted to 203. ESI MS m/z=358.1
(M+1). .sup.1H NMR (400 MHz, DMSO) .delta. 9.41 (s, 1H), 9.17 (s,
1H), 8.89 (d, J=2.2 Hz, 1H), 8.62-8.52 (m, 3H), 8.20 (dd, J=8.8,
2.3 Hz, 1H), 7.50 (dd, J=7.5, 5.1 Hz, 1H), 6.58 (d, J=8.8 Hz, 1H),
3.67-3.56 (m, 3H), 3.52-3.40 (m, 1H), 3.22-3.10 (m, 1H), 2.16-2.00
(m, 1H), 1.81-1.68 (m, 1H)
Example 204
3-(pyridin-2-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine
204
[0296] To a microwave tube was added
3-iodo-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine from Example 4
(120 mg, 0.37 mmol), 2-(butyldipentylstannyl)pyridine (168 mg, 0.45
mmol), Pd(PPh).sub.3 (12 mg, 0.015 mmol), LiCl (48 mg, 1.14 mmol),
CuI (12 mg, 0.06 mmol) and 1,4-dioxane (0.3 mL). The tube was
flushed with nitrogen for 2 minutes and heated in a Biotage
microwave at 140.degree. C. for 15 minutes. The solvent was
distilled off and the crude product was purified via reverse phase
combiflash eluting with 10% to 80% CH.sub.3CN in aqueous 0.5%
NH.sub.4OH solution to afford 204 as a pale red solid (11 mg, 11%).
.sup.1H NMR (400 MHz, DMSO) .sup.1H NMR (500 MHz, DMSO) .delta.
14.0 (s, 1H), 9.30 (s, 1H), 9.25 (s, 1H), 8.97 (s, 1H), 8.81 (d,
=4.0 Hz, 1H), 8.62-8.61 (m, 1H), 8.45 (d, J=8.5 Hz, 1H), 8.22 (d,
J=7.5 Hz, 1H), 7.97-7.94 (m, 1H), 7.55-7.53 (m, 1H), 7.45-7.43 (m,
1H). ESI MS m/z=274 (M+1)
Example 205
3-(2-fluoro-5-methylphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c-
]pyridine 205
[0297] Following the procedures in Example 172,
2-fluoro-5-methylphenylboronic acid and
3-chloro-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyr-
azolo[3,4-c]pyridine were reacted and deprotected to give 205 as a
white solid (21.3% over two steps). .sup.1H NMR (400 MHz, DMSO)
.delta. (400 MHz, DMSO) .delta. 13.86 (s, 1H), 9.05 (s, 1H), 8.25
(s, 1H), 7.98 (s, 1H), 7.88 (d, J=2.7 Hz, 1H), 7.63 (d, J=6.3 Hz,
1H), 7.36-7.27 (m, 2H), 3.88 (s, 3H), 2.40 (s, 3H). LC/MS: m/z
308.0 [M+1]
Example 206
(S)-1-(6-(5-(5-fluoropyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin--
2-yl)piperidin-3-amine 206
[0298] A solution containing
3-(6-fluoropyridin-2-yl)-5-(5-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran--
2-yl)-1H-pyrazolo[3,4-c]pyridine (0.055 g, 0.14 mmol) and
(S)-tert-butyl piperidin-3-ylcarbamate (0.196 g, 0.979 mmol) in
Dimethyl sulfoxide (0.840 mL, 11.8 mmol) was heated at 95.degree.
C. for 18 h. The reaction was quenched with water and then
extracted with EtOAc 2.times.. The combined organic layer was dried
with Na2SO4, filtered and concentrated. The crude product was dried
under high vacuum overnight to give tert-butyl
(3S)-1-(6-(5-(5-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyraz-
olo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-3-ylcarbamate which
was dissolved in 1,4-Dioxane (1.50 mL, 19.2 mmol) and treated with
4.0 M of Hydrogen chloride in 1,4-Dioxane (2.50 mL). The reaction
was stirred at RT for 18 h. The reaction was concentrated then
submitted for rHPLC to give 206 (37.8 mg, 69% yield). ESI MS
m/z=390.1 (M+1). .sup.1H NMR (400 MHz, DMSO) .delta. 9.22 (s, 1H),
9.18 (s, 1H), 9.03 (s, 1H), 8.60 (d, J=2.7 Hz, 1H), 8.32 (d, J=10.3
Hz, 1H), 7.66 (t, J=8.0 Hz, 1H), 7.45 (d, 0.1=7.4 Hz, 1H), 6.87 (d,
0.1=8.5 Hz, 1H), 4.37-4.25 (m, 2H), 3.08-2.96 (m, 1H), 2.85-2.75
(m, 2H), 2.00-1.88 (m, 1H), 1.85-1.75 (m, 1H), 1.68-1.56 (m, 1H),
1.42-1.25 (m, 1H)
Example 208
5-(5-fluoropyridin-3-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,-
4-c]pyridine 208
[0299] Following the procedures in Example 206,
3-(6-fluoropyridin-2-yl)-5-(5-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran--
2-yl)-1H-pyrazolo[3,4-c]pyridine was converted to 208. ESI MS
m/z=376.1 (M+1). .sup.1H NMR (400 MHz, DMSO) .delta. 9.23 (s, 1H),
9.12 (s, 1H), 9.02 (s, 1H), 8.61 (d, J=2.7 Hz, 1H), 8.23 (d, J=10.4
Hz, 1H), 7.69 (t, J=7.9 Hz, 1H), 7.49 (d, J=7.4 Hz, 1H), 6.88 (d,
J=8.5 Hz, 1H), 3.67-3.60 (m, 4H), 2.94-2.86 (m, 4H
Example 210
(R)-1-(6-(5-(5-fluoropyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin--
2-yl)piperidin-3-amine 210
[0300] Following the procedures in Example 206,
3-(6-fluoropyridin-2-yl)-5-(5-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran--
2-yl)-1H-pyrazolo[3,4-c]pyridine was converted to 210. ESI MS
m/z=390.1 (M+1). .sup.1H NMR (400 MHz, DMSO) .delta. 9.23 (s, 1H),
9.18 (s, 1H), 9.02 (s, 1H), 8.60 (d, J=2.7 Hz, 1H), 8.32 (d, J=10.4
Hz, 1H), 7.66 (t, J=8.0 Hz, 1H), 7.45 (d, J=7.4 Hz, 1H), 6.87 (d,
J=8.5 Hz, 1H), 4.39-4.23 (m, 2H), 3.08-2.98 (m, 1H), 2.86-2.74 (m,
2H), 1.99-1.88 (m, 1H), 1.71-1.65 (m, 1H), 1.62-1.58 (m, 1H),
1.38-1.30 (m, 1H)
Example 212
3-(6-(piperazin-1-yl)pyridin-2-yl)-5-(tetrahydrofuran-3-yl)-1H-pyrazolo[3,-
4-c]pyridine 212
[0301] Following the procedures in Example 206,
3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-5-(tetrahydrofuran--
3-yl)-1H-pyrazolo[3,4-c]pyridine was converted to 212. ESI MS
m/z=351.1 (M+1). .sup.1H NMR (400 MHz, DMSO) .delta. 9.02 (s, 1H),
8.29 (s, 1H), 7.66 (t, J=7.9 Hz, 1H), 7.46 (d, J=7.4 Hz, 1H), 6.84
(d, J=8.5 Hz, 1H), 4.13 (t, J=7.6 Hz, 1H), 3.99-3.83 (m, 2H),
3.80-3.60 (m, 2H), 3.65-3.60 (m, 4H), 3.00-2.92 (m, 4H), 2.45-2.35
(m, 1H), 2.25-2.15 (m, 1H)
Example 213
5-(1H-imidazol-5-yl)-3-phenyl-1H-pyrazolo[3,4-c]pyridine 213
[0302] Following the procedures in Example 204,
1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl)-1H-imidazole and
5-bromo-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine
were reacted and the product was deprotected to give 213 as a
yellow solid (30 mg, 25%) over two steps. .sup.1H NMR (400 MHz,
DMSO) .delta. 8.23 (s, 1H), 7.75 (s, 1H), 7.43 (m, 1H), 7.34 (m,
1H), 7.27 (m, 2H), 6.77 (m, 2H), 6.66 (m, 1H). ESI MS m/z=262
(M+1)
Example 214
3-phenyl-5-(pyrazin-2-yl)-1H-pyrazolo[3,4-c]pyridine 214
[0303] Following the procedures in Example 204,
2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine and
5-bromo-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine
were reacted and the product was deprotected to give 214 as a
yellow solid (22 mg, 28%) over two steps. .sup.1H NMR (400 MHz,
DMSO) .delta. 9.61 (s, 1H), 9.26 (s, 1H), 8.97 (s, 1H), 8.76 (s,
1H), 8.67 (d, 1H), 8.05 (t, 2H), 7.61 (t, 2H), 7.48 (t, 1H). ESI MS
m/z=274 (M+1)
Example 215
3-(1-(piperidin-4-yl)-1H-pyrazol-3-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]-
pyridine 215
Step 1:
5-bromo-3-(1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazo-
lo[3,4-c]pyridine
##STR00479##
[0305] A microwave reaction vial was charged with
5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine
(408.03 mg, 1.0 mmol), 1H-pyrazol-3-ylboronic acid (117.49 mg, 1.05
mmol), 1,1'-Bis(diphenylphosphino)ferrocenepalladium (II) chloride
(81.66 mg, 0.1 mmol), 1.00 M of Potassium acetate in Water (1.5 mL,
1.5 mmol), 1.00 M of Sodium carbonate in Water (1.5 mL, 1.5 mmol),
and Acetonitrile (3 mL). The reaction mixture was heated under
microwave at 100.degree. C. for 20 minutes. Added another 2
equivalents of 1H-pyrazol-3-ylboronic acid and continue heated
under microwave at 100.degree. C. for 20 minutes. The same
procedure was repeated 2 more times. The mixture was concentrated
and the residue was purified on silica eluted with 0 to 100% Ethyl
acetate in Heptane to afford
5-bromo-3-(1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4--
c]pyridine as an off-white solid (153.7 mg, 44%).
Step 2:
3-(1H-pyrazol-3-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)--
1H-pyrazolo[3,4-c]pyridine
##STR00480##
[0307] A microwave reaction vials was charged with
5-bromo-3-(1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4--
c]pyridine as an off-white solid (153.7 mg 0.44 mmol),
3-Pyridylboronic acid (81.62 mg, 0.66 mmol),
1,1'-Bis(diphenylphosphino)ferrocenepalladium (II) chloride (36.15
mg, 0.044 mmol), 1.00 M of Potassium acetate in Water (0.66 mL,
0.66 mmol), 1.00 M of Sodium carbonate in Water (0.66 mL, 0.66
mmol), and Acetonitrile (3 mL). The reaction mixture was heated
under microwave at 130.degree. C. for 20 minutes. The mixture was
concentrated and the residue was purified on silica eluted with 0
to 7% MeOH in DCM with 1% NH4OH to afford
3-(1H-pyrazol-3-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyra-
zolo[3,4-c]pyridine (73.4 mg, 48%).
Step 3: tert-butyl
4-(3-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyr-
idin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate
##STR00481##
[0309] A mixture of
3-(1H-pyrazol-3-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyra-
zolo[3,4-c]pyridine (44.0 mg, 0.13 mmol), 1-N-BOC-4-bromopiperidine
(100.8 mg, 0.38 mmol), and Cesium Carbonate (124.3 mg, 0.38 mmol)
in N,N-Dimethylformamide (5 mL) was heated at 100.degree. C. for 7
days. The mixture was concentrated to afford tert-butyl
44345-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyrid-
in-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate, which was used
without purification.
Step 4
[0310] Tert-butyl
4-(3-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyr-
idin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (17.0 mg, 0.032
mmol) in Dioxane (5 mL) was treated with 4.0 M of Hydrogen chloride
in 1,4-Dioxane (5 mL) overnight at room temperature. The reaction
mixture was concentrated, and the residue was purified by reverse
phase HPLC to afford 215 as an off-white solid (1.2 mg, 18%). 1H
NMR (400 MHz, DMSO) .delta. 9.28 (s, 1H), 9.19 (s, 1H), 8.70-8.57
(m, 2H), 8.44 (d, J=7.6 Hz, 1H), 8.30 (s, 1H), 7.94 (s, 1H),
7.59-7.51 (m, 1H), 6.84 (s, 1H), 4.47 (s, 1H), 3.22 (d, J=12.7 Hz,
2H), 2.82 (t, J=12.0 Hz, 2H), 2.15 (d, J=11.5 Hz, 2H), 2.04 (d,
J=9.0 Hz, 2H). ESI MS m/z=346.1 (M+1)
Example 216
3-(6-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)-5-(1-methyl-
-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine 216
[0311] Following the procedures as described in Example 189,
3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-py-
ran-2-yl)-1H-pyrazolo[3,4-c]pyridine and
2-(1-trityl-1H-imidazol-4-yl)-ethylamine were reacted. The product
was deprotected to give 216 as a white solid (69.7% over two
steps). .sup.1H NMR (400 MHz, DMSO) .delta. 9.02 (s, 1H), 8.59 (s,
1H), 8.11 (s, 1H), 7.84 (s, 1H), 7.59 (t, J=7.9 Hz, 1H), 7.36 (d,
J=7.4 Hz, 1H), 6.64 (broad s, 1H), 6.50 (d, J=8.2 Hz, 1H), 4.76 (s,
1H), 3.91 (s, 3H), 3.75 (s, 1H), 3.69 (d, J=8.5 Hz, 1H), 3.49-3.32
(m, 2H), 3.00 (s, 2H), 1.89 (d, J=8.5 Hz, 1H), 1.78 (d, J=9.1 Hz,
1H). LC/MS: m/z 373.1 [M+1]
Example 217
N-(2-(1H-imidazol-4-yl)ethyl)-6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[-
3,4-c]pyridin-3-yl)pyridin-2-amine 217
[0312] Following the procedures as described in Example 189,
3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-py-
ran-2-yl)-1H-pyrazolo[3,4-c]pyridine and
2-(1-trityl-1H-imidazol-4-yl)-ethylamine were reacted. The product
was deprotected to give 217 as a white solid (37.6% over two
steps). .sup.1H NMR (400 MHz, DMSO) .delta. 9.01 (s, 1H), 8.62 (s,
1H), 8.26 (s, 1H), 8.03 (s, 1H), 7.88 (s, 1H), 7.56 (s, 1H), 7.49
(d, J=8.1 Hz, 1H), 7.34 (d, J=7.4 Hz, 1H), 6.86 (s, 1H), 6.80 (s,
1H), 6.49 (d, J=8.3 Hz, 1H), 3.88 (s, 3H), 3.78-3.70 (m, 2H), 2.92
(t, J=7.5 Hz, 2H), 2.54 (s, 1H). LC/MS: m/z 386.1 [M+1]
Example 218
3-(2-fluorophenyl)-5-(1H-imidazol-5-yl)-1H-pyrazolo[3,4-c]pyridine
218
Step 1:
5-bromo-3-(2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-
o[3,4-c]pyridine
##STR00482##
[0314] To a microwave tube was added
5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine
(300 mg, 0.74 mmol), 2-fluorophenylboronic acid (134 mg, 0.96
mmol), Pd(dppf) Cl.sub.2 (60 mg, 0.07 mmol), sodium carbonate (314
mg, 2.96 mmol), 1,2-dimethoxyethane (3 mL), ethanol (0.3 mL) and
water (0.3 mL). The tube was flushed with nitrogen for 2 minutes
and heated in a Biotage microwave at 145.degree. C. for 1 hour. The
solvent was distilled off and the crude product was purified via
flash chromatography eluting with 20% to 95% ethyl acetate in
petroleum to afford
5-bromo-3-(2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c-
]pyridine as a yellow oil (105 mg, 38%). ESI MS m/z=377 (M+1).
Step 2:
3-(2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-5-(1-(tetrahydro-2-
H-pyran-2-yl)-1H-imidazol-5-yl)-1H-pyrazolo[3,4-c]pyridine
##STR00483##
[0316] To a 100 mL of round bottom flask was added
5-bromo-3-(2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c-
]pyridine (150 mg, 0.40 mmol),
1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl)-1H-imidazole (222 mg, 0.80 mmol), Pd(PPh.sub.3).sub.4 (33 mg,
0.04 mmol), CsF (152 mg, 1 mmol), CuI (8 mg, 0.04 mmol) and DMF (6
mL). The reaction mixture was heated at 90.degree. C. under
nitrogen for overnight. The resulting mixture was poured into 50 mL
of water and extracted with ethyl acetate (50 mL.times.3). The
combined organic layers were washed with brine, dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue
was purified via flash chromatography eluting with 5% to 10%
CH.sub.3OH in CH.sub.2Cl.sub.2 to afford
3-(2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-5-(1-(tetrahydro-2H-pyran-
-2-yl)-1H-imidazol-5-yl)-1H-pyrazolo[3,4-c]pyridine as a brown oil
(100 mg, 84%). ESI MS m/z=448 (M+1).
Step 3
[0317] In a 50 mL round bottom flask was added
3-(2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-5-(1-(tetrahydro-2H-pyran-
-2-yl)-1H-imidazol-5-yl)-1H-pyrazolo[3,4-c]pyridine (150 mg, 0.33
mmol) and 4 N HCl-- dioxane (5 mL). The mixture was stirred at
25.degree. C. for 2 h. The solvent was distilled off. The crude
product was purified via reverse phase HPLC eluting with 35%
CH.sub.3CN in aqueous 10 mmol NH.sub.4HCO.sub.3 solution to afford
218 as a white solid (20 mg, 21%). .sup.1H NMR (500 MHz, DMSO)
.delta. 13.93 (s, 1H), 12.21 (s, 1H), 9.05 (s, 1H), 8.20 (s, 1H),
7.86 (t, J=7.0, 1H), 7.71 (s, 1H), 7.62 (s, 1H), 7.56-7.54 (m, 1H),
7.46 (t, J=10.0, 1H), 7.41 (t, J=7.5, 1H). ESI MS m/z=280 (M+1)
Example 219
3-(2-fluorophenyl)-5-(pyrazin-2-yl)-1H-pyrazolo[3,4-c]pyridine
219
[0318] Following the procedures as described in Example 218, and
starting with
3-(2-fluorophenyl)-5-(pyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H--
pyrazolo[3,4-c]pyridine, 219 was obtained as a pale red solid (16
mg, 20%) over two steps. .sup.1H NMR (500 MHz, DMSO) .delta. 9.60
(s, 1H), 9.27 (s, 1H), 8.77 (s, 1H), 8.73 (s, 1H), 8.67 (s, 1H),
7.93-7.90 (m, 1H), 7.60-7.56 (m, 1H), 7.49 (t, J=8.0, 1H), 7.43 (t,
J=8.0, 1H). ESI MS m/z=292 (M+1)
Example 222
(R)-1-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)phen-
yl)piperidin-3-amine 222
Step 1: tert-butyl
(3R)-1-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-p-
yrazolo[3,4-c]pyridin-3-yl)phenyl)piperidin-3-ylcarbamate
##STR00484##
[0320] Following the Suzuki coupling procedure in Example 172,
(R)-tert-butyl
1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-3-ylca-
rbamate and
3-chloro-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyr-
azolo[3,4-c]pyridine were reacted to give tert-butyl
(3R)-1-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-p-
yrazolo[3,4-c]pyridin-3-yl)phenyl)piperidin-3-ylcarbamate as a
solid (60%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.12 (s,
1H), 7.97 (s, 1H), 7.95 (s, 1H), 7.93 (s, 1H), 7.34 (t, J=7.8 Hz,
1H), 7.26 (s, 1H), 7.19 (s, 1H), 6.73 (d, J=8.4 Hz, 1H), 5.90-5.83
(m, 1H), 4.09-4.00 (m, 2H), 3.97 (s, 3H), 3.88-3.76 (m, 2H), 3.67
(s, 1H), 3.52 (s, 1H), 3.17 (s, 1H), 3.03 (s, 1H), 2.64-2.52 (m,
1H), 2.17 (d, J=10.1 Hz, 2H), 2.09-1.99 (m, 1H), 1.84-1.70 (m, 5H),
1.65-1.54 (m, 1H), 1.41 (s, 9H). LC/MS: m/z 558.2 [M+1].
Step 2
[0321] Following the procedure in Example 189, tert-butyl
(3R)-1-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-p-
yra-zolo[3,4-c]pyridin-3-yl)phenyl)piperidin-3-ylcarbamate was
deprotected to give 222 as a solid (55.4%). .sup.1H NMR (400 MHz,
DMSO) .delta. 9.02 (s, 1H), 8.31 (s, 1H), 8.28 (s, 1H), 8.13 (s,
1H), 8.05 (s, 1H), 7.34-7.21 (m, 3H), 6.70-6.65 (m, 1H), 5.74 (d,
J=7.7 Hz, 1H), 3.90 (s, 3H), 3.24 (d, J=11.4 Hz, 1H), 2.96 (d,
J=12.3 Hz, 1H), 2.62 (t, J=11.4 Hz, 1H), 2.45 (d, J=10.7 Hz, 1H),
2.05-1.96 (m, 1H), 1.82-1.73 (m, 1H), 1.63-1.39 (m, 2H); 2 protons
not seen. LC/MS: m/z 374.1 [M+1]
Example 223
1-methyl-4-(3-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-
-yl)piperazin-2-one 223
[0322] Following the procedure of Example 224, tert-butyl
(3S)-1-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-
-3-yl)pyridin-2-yl)piperidin-3-ylcarbamate and
1-methylpiperazin-2-one were reacted and deprotected by the
procedure of Example 229. The mixture was purified by
lyophilization from water and trituration of the crude product with
cold methanol. The solid material was collected by filtration to
afford 52 mg (28%) of 223 over two steps. ESI MS m/z 393.2 (M+1).
.sup.1H NMR (400 MHz, DMSO) .delta. 13.55 (s, 1H), 9.07 (s, 2H),
8.81 (s, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.60 (s, 1H), 7.52 (d, J=7.5
Hz, 1H), 6.92 (d, J=8.5 Hz, 1H), 3.95 (s, 2H), 3.88 (m, 6H),
3.48-3.44 (m, 2H), 3.31 (s, 4H), 2.91 (s, 3H)
Example 224
1-(3-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)urea
224
Step 1: tert-Butyl
4-(6-(5-(3-tert-butylureido)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-
-c]pyridin-3-yl)pyridin-2-yl)piperazine-1-carboxylate
##STR00485##
[0324] A mixture of 109 mg (0.2 mmol) of tert-butyl
4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl-
)pyridin-2-yl)piperazine-1-carboxylate, 46.5 mg (0.40 mmol) of
(1,1-dimethylethyl)urea, 23 mg (0.040 mmol) of
4,5-bis(diphenylphosphino)-9,9-dimethylxantene and 130 mg (0.40
mmol) of cesium carbonate in 1 ml of dioxane was degassed and
heated for at 95.degree. C. for 30 min. The mixture was diluted
with 10 ml of dichloromethane and filtered through celite. The
filtrate was concentrated, the title compound was purified via
silica gel chromatography using a gradient of ethyl acetate in
heptane to afford 86 mg (74%). ESI MS m/z 579.2 (M+1) of tert-Butyl
4-(6-(5-(3-tert-butylureido)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-
-c]pyridin-3-yl)pyridin-2-yl)piperazine-1-carboxylate.
Step 2
[0325] tert-Butyl
4-(6-(5-(3-tert-butylureido)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-
-c]pyridin-3-yl)pyridin-2-yl)piperazine-1-carboxylate was
deprotected by the procedure of Example 229 and purified via
reverse phase HPLC using a gradient of MeOH in water with 0.1%
NH.sub.4OH to afford 17 mg (25%) of 224 over two steps. ESI MS m/z
339.1 (M+1). 1H NMR (400 MHz, DMSO): 13.71-13.30 (s, 1H), 8.93 (s,
1H), 8.74 (d, J=10.4 Hz, 2H), 7.52 (m, 1H), 7.41 (d, J=7.4 Hz, 1H),
6.76 (d, J=8.4 Hz, 1H), 6.34 (s, 2H), 3.57 (s, 2H), 2.87 (d, J=4.7
Hz, 2H)
Example 225
3-cyclopentenyl-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine 225
Step 1:
3-Cyclopentenyl-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-p-
yrazolo[3,4-c]pyridine
##STR00486##
[0327] Following the Suzuki coupling procedure of Example 159,
5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine
and 2-cyclopentenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were
reacted. The product was reacted with 3-pyridineboronic acid
pinacol ester by the Suzuki coupling procedure of Example 10 and
the mixture was purified via silica gel chromatography using a
gradient of ethyl acetate in heptane to afford 106 mg (61%) of
3-Cyclopentenyl-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo-
[3,4-c]pyridine over two steps. ESI MS m/z 347.3 (M+1).
Step 2
[0328] A mixture of 35 mg (0.10 mmol) of
3-cyclopentenyl-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo-
[3,4-c]pyridine in 4 ml of trifluoroacetic acid was stirred for 6
hours. The mixture was concentrated in vacuum, the residue
partitioned between saturated aqueous solution of NaHCO3 and ethyl
acetate. The organic extracts were washed with water, brine, dried
over MgSO4 and concentrated. The residue was purified via reverse
phase HPLC using a gradient of MeOH in water with 0.1% NH.sub.4OH
to afford 10 mg (38%) of 225. ESI MS m/z 263.0 (M+1). 1H NMR (400
MHz, DMSO): 13.59 (s, 1H), 9.39 (s, 1H), 9.14 (s, 1H), 8.53-8.600
(m, 3H), 7.50 (dd, J=7.9, 4.8 Hz, 1H), 6.88 (s, 1H), 2.91 (t, J=6.6
Hz, 2H), 2.64 (s, 2H), 2.04-1.94 (m, 2H)
Example 226
1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin--
2-yl)azepan-3-amine 226
[0329] Following the procedures as described in Example 189,
3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-py-
ran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl
azepan-3-ylcarbamate were reacted. The product was deprotected to
give 226 as a white solid (58.6% over two steps). .sup.1H NMR (400
MHz, DMSO) .delta. 9.04 (s, 1H), 8.52 (s, 1H), 8.32 (s, 1H), 8.28
(s, 1H), 7.94 (s, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.43 (d, J=7.4 Hz,
1H), 6.75 (d, J=8.5 Hz, 1H), 4.18 (d, J=12 Hz, 1H), 4.13-4.06 (m,
1H), 3.90 (s, 3H), 3.54 (m, 1H), 3.36 (d, J=8.8 Hz, 1H), 3.32 (s,
1H), 2.05-1.95 (m, 1H), 1.84-1.69 (m, 3H), 1.53-1.41 (m, 1H),
1.40-1.27 (m, 1H); 2 protons not seen. LC/MS: m/z 389.2 [M+1]
Example 227
(S)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyri-
din-2-yl)azepan-4-amine 227
Step 1: benzyl
(4S)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-p-
yrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-ylcarbamate
[0330] Following the procedure of Example 189, (S)-benzyl
azepan-4-ylcarbamate and
3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-py-
ran-2-yl)-1H-pyrazolo[3,4-c]pyridine were reacted to give benzyl
(4S)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-p-
yrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-ylcarbamate as a
solid (73.4%). LC/MS: m/z 607.3 [M+1].
Step 2
[0331] To a solution of benzyl
(4S)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-p-
yrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-ylcarbamate (70.0
mg, 0.13 mmol) in DCM (5.0 mL) at -10.degree. C. was added dropwise
1 M of boron tribromide in DCM (0.33 mL, 0.33 mmol), and the
reaction mixture was slowly warmed to room temperature (RT) and
stirred at RT under N.sub.2 for 16 h. The reaction mixture was
diluted into ethyl acetate and water. The organic layer was washed
with aqueous saturated sodium bicarbonate solution, water and
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated
under reduced pressure. The crude was redissolved in DMSO (1 mL)
and was purified by reverse phase HPLC to give 227 as a white solid
(4.3 mg, 8.3%). .sup.1H NMR (400 MHz, DMSO) .delta. 9.03 (s, 1H),
8.55 (s, 1H), 8.11 (s, 1H), 7.83 (s, 1H), 7.60 (t. J=7.8 Hz, 1H),
7.37 (d, J=7.1 Hz, 1H), 6.61 (d, J=8.4 Hz, 1H), 3.91 (s, 3H),
3.85-3.75 (m, 1H), 3.74-3.58 (m, 2H), 3.33-3.40 (m, 1H), 2.95-2.85
(m, 1H), 2.12-1.93 (m, 2H), 1.86-1.58 (m, 3H), 1.56-1.33 (m, 2H); 2
protons not seen. LC/MS: m/z 389.4 [M+1]
Example 228
3-cyclopentyl-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine 228
Step 1:
3-Cyclopentyl-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyr-
azolo[3,4-c]pyridine
##STR00487##
[0333] A mixture of 42 mg (0.12 mmol) of
3-cyclopentenyl-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo-
[3,4-c]pyridine, 2.0 ml (21 mmol) of 1,4-cyclohexadiene and 100 mg
of 10% palladium on carbon in 10 ml of ethanol was heated to reflux
for 48 hours, during which 1,4-cyclohexadiene was added
incrementally. The mixture was filtered through celite, and the
filtrate was concentrated to afford 31 mg (76%) of
3-Cyclopentyl-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3-
,4-c]pyridine. ESI MS m/z 349.2 (M+1).
Step 2
[0334]
3-Cyclopentyl-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyra-
zolo[3,4-c]pyridine was deprotected by the procedure of Example 229
and purified by triturating with ethyl ether. The product was
collected by filtration to afford 9 mg (30%) of 228. ESI MS m/z
265.0 (M+1). 1H NMR (400 MHz, DMSO): 13.24 (s, 1H), 9.33 (s, 1H),
9.08 (s, 1H), 8.56 (d, J=4.2 Hz, 1H), 8.48 (d, J=8.0 Hz, 1H), 8.40
(s, 1H), 7.50 (m, 1H), 3.54 (dd, J=16.4, 8.2 Hz, 1H), 2.16 (m, 2H),
2.00-1.63 (m, 6H)
Example 229
4-amino-1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl-
)piperidine-4-carboxamide 229
Step 1: Methyl
4-(tert-butoxycarbonylamino)-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyra-
n-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidine-4-carboxyla-
te
##STR00488##
[0336] Following the procedures of Example 144, and starting with
3-(6-Fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-
-pyrazolo[3,4-c]pyridine and methyl
4-(tert-butoxycarbonylamino)piperidine-4-carboxylate were reacted
and purified via silica gel chromatography using a gradient of
EtOAc in heptane to afford 241 mg (67%) of Methyl
4-(tert-butoxycarbonylamino)-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyra-
n-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidine-4-carboxyla-
te. ESI MS m/z 614.2 (M+1).
Step 2:
4-(tert-Butoxycarbonylamino)-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro--
2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidine-4-ca-
rboxylic acid
##STR00489##
[0338] A mixture of 240 mg (0.39 mmol) of methyl
4-(tert-butoxycarbonylamino)-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyra-
n-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidine-4-carboxyla-
te and 3 ml of 1 M aqueous solution of lithium hydroxide in 20 ml
of methanol and 10 ml of tetrahydrofuran was stirred for 18 hours
at room temperature and 2 hours at 60.degree. C. The mixture was
concentrated in vacuum, neutralized to pH 5 by careful addition of
1 N aqueous HCl and extracted with ethyl acetate. The organic
extracts were washed with water, brine, dried over MgSO4 and
concentrated to afford 150 mg (43%) of
4-(tert-Butoxycarbonylamino)-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyra-
n-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidine-4-carboxyli-
c acid over two steps. ESI MS m/z 600.2 (M+1).
Step 3: tert-Butyl
4-carbamoyl-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazo-
lo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-4-ylcarbamate
##STR00490##
[0340] N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium
hexafluorophosphate 45.6 mg, 0.120 mmol) was added to a mixture of
4-(tert-butoxycarbonylamino)-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyra-
n-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidine-4-carboxyli-
c acid (60.0 mg, 0.100 mmol), ammonium chloride 21 mg (0.40 mmol)
and N,N-Diisopropylethylamine (0.087 ml, 0.50 mmol) in 2 ml of
N,N-dimethylformamide. The mixture was stirred for 18 hours and
concentrated. The residue was partitioned between ethyl acetate and
1% of aqueous citric acid. The organic extracts were washed with
water, 5% aqueous solution of NaHCO3, brine, dried over MgSO4 and
concentrated to give tert-Butyl
4-carbamoyl-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazo-
lo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-4-ylcarbamate. Yield
47 mg (78%). ESI MS m/z 599.2 (M+1).
Step 4
[0341] A mixture of 45 mg (0.08 mmol) of tert-butyl
4-carbamoyl-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazo-
lo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-4-ylcarbamate in 3 ml
of methanol and 12 ml of 4 N solution of HCl in dioxane was stirred
for 18 hours. The mixture was concentrated in vacuum, the residue
purified via reverse phase HPLC using a gradient of MeCN in water
with 0.1% HCOOH to afford 20 mg (43%) of 229. ESI MS m/z 415.2
(M+1). 1H NMR (400 MHz, DMSO): 9.22 (d, J=5.7 Hz, 2H), 8.94 (s,
1H), 8.60 (d, J=4.6 Hz, 1H), 8.40-8.32 (m, 4H), 7.67 (t, J=7.9 Hz,
1H), 7.54 (dd, J=8.0, 4.8 Hz, 1H), 7.46 (d, J=7.4 Hz, 1H), 6.95 (s,
1H), 6.90 (d, J=8.5 Hz, 1H), 4.20 (d, J=13.2 Hz, 1H), 3.50 (t,
J=11.4 Hz, 1H), 2.06 (td, J=13.0, 4.2 Hz, 1H), 1.48 (d, J=13.2 Hz,
1H).
Example 232
3-(1-methyl-1H-pyrazol-3-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine
232
Step 1:
3-(1-methyl-1H-pyrazol-3-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsily-
l)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine
##STR00491##
[0343] In a microwave reaction vials was charged with
3-iodo-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[-
3,4-c]pyridine (49.10 mg, 0.11 mmol),
1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(33.19 mg, 0.16 mmol),
1,1'-Bis(diphenylphosphino)ferrocenepalladium (II) chloride (8.68
mg, 0.011 mmol), 1.00 M of Potassium acetate in Water (0.16 mL,
0.16 mmol), 1.00 M of Sodium carbonate in Water (0.16 mL, 0.16
mmol), and Acetonitrile (3 mL). The reaction mixture was heated
under microwave at 150.degree. C. for 5 minutes. The mixture was
concentrated to afford
3-(1-methyl-1H-pyrazol-3-yl)-5-(pyridin-3-yl)-1-((2-(trimethyls-
ilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine, which was used
without purification.
Step 2
[0344] A solution of
3-(1-methyl-1H-pyrazol-3-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethox-
y)methyl)-1H-pyrazolo[3,4-c]pyridine (43.22 mg, 0.1063 mmol) in
Dioxane (5 mL) was treated with 4.0 M of Hydrogen chloride in
1,4-Dioxane (5 mL) overnight at room temperature. The reaction
mixture was concentrated, and the residue was purified by reverse
phase HPLC to afford 232 as an off-white solid (23.7 mg, 81%). 1H
NMR (400 MHz, DMSO) .delta. 13.74 (s, 1H), 9.33 (s, 1H), 9.19 (s,
1H), 8.67 (d, J=11.2 Hz, 2H), 8.56 (d, J=7.9 Hz, 1H), 7.85 (s, 1H),
7.63 (s, 1H), 6.82 (s, 1H), 4.01 (s, 3H). ESI MS m/z=277.0
(M+1)
Example 234
5-(1-methyl-1H-pyrazol-4-yl)-3-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazol-
o[3,4-c]pyridine 234
[0345] Following the procedures as described in Example 189,
3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-py-
ran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl
1-piperazinecarboxylate were reacted. The product was deprotected
to give 234 as a white solid (61% over two steps). .sup.1H NMR (400
MHz, DMSO) .delta. 9.03 (s, 1H), 8.53 (s, 1H), 8.11 (s, 1H), 7.82
(s, 1H), 7.65 (t, J=7.9 Hz, 1H), 7.45 (d, J=7.2 Hz, 1H), 6.83 (d,
J=8.5 Hz, 1H), 3.91 (s, 3H), 3.63 (s, 4H), 2.94 (s, 4H); two
protons not seen. LC/MS: m/z 361.1 [M+1]
Example 235
2-(3-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)aceto-
nitrile 235
Step 1: tert-Butyl
4-(6-(5-(cyanomethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyri-
din-3-yl)pyridin-2-yl)piperazine-1-carboxylate
##STR00492##
[0347] A solution of 0.940 mL of 1.6 M of n-Butyllithium in hexane
was added dropwise to a solution of 0.102 mL, (1.95 mmol) of
acetonitrile in tetrahydrofuran at -78.degree. C. The mixture was
stirred for 30 min and a solution of 272 mg (0.500 mmol) of
4-{6-[5-bromo-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl]-p-
yridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester was
added. The brown mixture was stirred for 30 min at -50.degree. C.
and 2 ml of saturated aqueous NH4Cl was added. The mixture was
allowed to warm to room temperature and extracted with ethyl
acetate. The organic extracts were washed with water, brine, dried
over MgSO4 and concentrated. The residue was purified via silica
gel chromatography using a gradient of ethyl acetate in heptane to
afford 44 mg (17%) of tert-Butyl
4-(6-(5-(cyanomethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyri-
din-3-yl)pyridin-2-yl)piperazine-1-carboxylate. ESI MS m/z 504.2
(M+1).
Step 2
[0348] tert-Butyl
4-(6-(5-(cyanomethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyri-
din-3-yl)pyridin-2-yl)piperazine-1-carboxylate was deprotected
following the procedure of Example 225 and purified via reverse
phase HPLC using a gradient of MeOH in water with 0.1% NH.sub.4OH
to afford 10.4 mg (6.5%) of 235 over two steps. ESI MS m/z 320.1
(M+1). .sup.1H NMR (400 MHz, DMSO) .delta. 13.34 (s, 1H), 7.62 (dd,
J=8.4, 4.1 Hz, 1H), 7.04 (d, J=7.2 Hz, 1H), 6.98 (d, J=9.1 Hz, 1H),
6.79 (d, J=8.6 Hz, 1H), 5.98 (s, 1H), 3.63 (s, 2H), 2.92 (s,
2H)
Example 236
4-amino-N-methyl-1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyr-
idin-2-yl)piperidine-4-carboxamide 236
[0349] Following the procedures of Example 229, and starting with
4-(tert-butoxycarbonylamino)-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyra-
n-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidine-4-carboxyli-
c acid and methylamine, were reacted and purified via reverse phase
HPLC using a gradient of MeCN in water with 0.1% HCOOH to afford 19
mg (24%) of 236 over two steps. ESI MS m/z 429.2 (M+1). 1H NMR (400
MHz, DMSO): 13.95 (s, 1H), 9.22 (d, J=8.4 Hz, 2H), 8.92 (s, 1H),
8.61 (s, 1H), 8.41 (d, J=7.6 Hz, 1H), 8.28 (s, 1H), 8.13 (s, 1H),
7.72 (t, J=7.9 Hz, 1H), 7.52 (d, J=7.6 Hz, 2H), 6.96 (d, J=8.3 Hz,
1H), 6.49 (s, 1H), 4.27 (d, J=13.0 Hz, 2H), 3.53 (t, J=12.5 Hz,
2H), 2.67 (s, 3H), 2.29 (m, 2H), 1.87-1.73 (m, 2H).
Example 237
(R)-2-(1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)-
piperidin-3-yl)ethanamine 237 and Example 242
(S)-2-(1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl-
)piperidin-3-yl)ethanamine 242
[0350] Following the procedures of Example 149, and starting with
3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-
-pyrazolo[3,4-c]pyridine and racemic tert-butyl
2-(piperidin-3-yl)ethylcarbamate, 237 and 242 were obtained and
purified via reverse phase HPLC using a gradient of MeOH in water
with 0.1% NH.sub.4OH followed by SFC separation of the enantiomers
to afford 27 mg (14%) and 23 mg (12%).
[0351] ESI MS m/z 400.2 (M+1). 1H NMR (400 MHz, DMSO): 9.24 (d,
0.1=8.8 Hz, 2H), 8.96 (s, 1H), 8.61 (s, 1H), 8.42 (d, J=8.2 Hz,
1H), 7.67 (t, J=7.9 Hz, 1H), 7.60-7.52 (m, 1H), 7.47 (d, J=7.1 Hz,
1H), 6.90 (d, J=8.5 Hz, 1H), 4.34 (t, J=11.3 Hz, 2H), 3.00 (m, 2H),
2.83-2.76 (m, 2H), 1.91-1.19 (m, 5H).
[0352] ESI MS m/z 400.2 (M+1). 1H NMR (400 MHz, DMSO): 9.23 (d,
J=9.3 Hz, 2H), 8.95 (s, 1H), 8.60 (s, 1H), 8.41 (d, J=7.9 Hz, 1H),
7.66 (t, J=7.6 Hz, 1H), 7.56 (s, 1H), 7.46 (d, J=6.3 Hz, 1H), 6.88
(d, J=7.9 Hz, 1H), 4.30 (t, J=10.7 Hz, 2H), 3.02 (m, 2H), 2.75-2.68
(m, 2H), 1.88-1.17 (m, 5H)
Example 238
3-(3-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)pyrid-
in-2-amine 238
Step 1: tert-Butyl
4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl-
)pyridin-2-yl)piperazine-1-carboxylate
##STR00493##
[0354] Following the procedures of Example 144,
5-bromo-3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo-
[3,4-c]pyridine and tert-butyl piperazine-1-carboxylate were
reacted, triturated with ethyl ether, and collected by filtration
to afford 910 mg (80%) of tert-Butyl
4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl-
)pyridin-2-yl)piperazine-1-carboxylate. ESI MS m/z 543.2 (M+1).
Step 2
[0355] Following the Suzuki coupling procedure of Example 10,
5-bromo-3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo-
[3,4-c]pyridine and
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine were
reacted and the deprotected by the procedure of Example 229. The
crude compound was triturated with ethyl ether and collected by
filtration to afford 117 mg (81%) of 238. ESI MS m/z 373.1 (M+1).
1H NMR (400 MHz, DMSO): 14.25 (s, 1H), 9.39 (s, 2H), 9.25 (s, 1H),
8.85 (s, 1H), 8.77 (s, 2H), 8.45 (d, J=7.4 Hz, 1H), 8.13 (d, J=5.4
Hz, 1H), 7.79 (t, J=7.9 Hz, 1H), 7.60 (d, J=7.2 Hz, 1H), 7.11 (t,
1H), 7.01 (d, J=8.3 Hz, 1H), 3.91 (s, 2H), 3.28 (s, 2H)
Example 239
(1S,3R)--N1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2--
yl)cyclohexane-1,3-diamine 239
Example 245
(1S,3S)--N1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2--
yl)cyclohexane-1,3-diamine 245
[0356] Following the procedures of Example 143, and starting with
3-(6-Fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-
-pyrazolo[3,4-c]pyridine and a mixture of cis- and
trans-cyclohexanediamine, 239 and 245 were obtained and purified
via reverse phase HPLC using a gradient of MeOH in water with 0.1%
NH.sub.4OH followed by SFC separation of the enantiomers to afford
35 mg (29%) ESI MS m/z 386.1 (M+1), and 10 mg (8%). ESI MS m/z
386.1 (M+1).
Example 240
3-(piperazin-1-yl)-5-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)benz-
onitrile 240
[0357] Following the Suzuki coupling procedure of Example 159,
5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine
and tert-butyl
4-(3-cyano-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazi-
ne-1-carboxylate were reacted. The product was coupled with
3-pyridineboronic acid pinacol ester by the Suzuki coupling
procedure of Example 10 and deprotected by the procedure of Example
225. The mixture was purified via reverse phase HPLC using a
gradient of MeOH in water with 0.1% NH.sub.4OH to afford 37 mg
(19%) of 240 over three steps. ESI MS m/z 382.2 (M+1). 1H NMR (400
MHz, DMSO): 9.41 (s, 1H), 9.23 (s, 1H), 8.68-8.59 (m, 2H), 8.55 (d,
J=7.8 Hz, 1H), 7.87 (s, 1H), 7.80 (s, 1H), 7.56-7.50 (m, 1H), 7.43
(s, 1H), 3.26-3.23 (m, 4H), 2.87-2.81 (m, 4H)
Example 241
1-(3-chloro-6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-y-
l)piperidin-4-amine 241
Step 1:
5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(trimethyl-
stannyl)-1H-pyrazolo[3,4-c]pyridine
##STR00494##
[0359] To a mixture of
3-iodo-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[-
3,4-c]pyridine (3.3435 g, 7.3912 mmol) in Tetrahydrofuran (50 mL,
600 mmol) under Argon was added
trans-dichlorobis(triphenylphosphine) palladium (II) (259.39 mg,
0.36956 mmol), Hexamethylditin (1.6859 mL, 8.1303 mmol) and Lithium
chloride (1.8800 g, 44.347 mmol). The resulting mixture was
refluxed at 65.degree. C. for 2 hours. The mixture was cooled to
room temperature, filtered through Celite.RTM. and washed with
Ethyl acetate. The filtrated was concentrated, and the residue was
purified on silica eluted with 0 to 6% Methanol in dichloromethane
to afford
5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(trimethylstannyl-
)-1H-pyrazolo[3,4-c]pyridine as a yellow oil (2.2541 g,
62.33%).
Step 2:
3-(5-chloro-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethy-
lsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine
##STR00495##
[0361] To a solution of
5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(trimethylstannyl-
)-1H-pyrazolo[3,4-c]pyridine (1.3490 g, 2.7571 mmol) and
6-bromo-3-chloro-2-fluoropyridine (696.23 mg, 3.3086 mmol) in
tetrahydrofuran (10 mL, 100 mmol) under Argon in a pressure tube
was added Cesium fluoride (837.64 mg, 5.5143 mmol), Palladium(II)
Chloride (24.446 mg, 0.13786 mmol), Copper(I) iodide (52.510 mg,
0.27571 mmol), and 1.000 M of Tri-tert-butylphosphine in Toluene
(275.71 uL) at room temperature. The tube was sealed and the
mixture was heated at 45.degree. C. overnight. The mixture was
cooled to room temperature, and filtered through Celite.RTM.. The
filter cake was washed with ethyl acetate; the combined organic
layer was washed with brine, dried with MgSO4, and then
concentrated. The residue was purified on silica eluted with 0 to
100% EtOAc in Heptane to afford
3-(5-chloro-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)-
ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine as a yellow oil, which
solidified upon standing.
Step 3
[0362] In a pressure tube was charged with
3-(5-chloro-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)-
ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (103.4 mg, 0.2268 mmol),
4-(N-Boc-amino)-piperidine (136.24 mg, 0.6803 mmol),
4-Methylmorpholine (249.30 uL, 10 mmol), and N-Methylpyrrolidinone
(3 mL). The mixture was heated at 120.degree. C. overnight. The
reaction mixture was cooled to room temperature, diluted with
EtOAc, washed 3 times with water. The organic layer was dried with
MgSO4, and then concentrated. The residue was purified on silica
eluted with 0 to 100% EtOAc in DCM to afford tert-butyl
1-(3-chloro-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-p-
yrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-4-ylcarbamate. It
was dissolved in 1,4-Dioxane (5 mL) and treated with 4.0 M of
Hydrogen chloride in 1,4-Dioxane (5 mL) overnight. The mixture was
concentrated, and the residue was purified by reverse phase HPLC to
afford 241 as an off-white solid (8.7 mg, 19%). 1H NMR (400 MHz,
DMSO) .delta. 9.24 (d, J=10.3 Hz, 2H), 8.99 (s, 1H), 8.61 (s, 1H),
8.42 (d, J=7.5 Hz, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.77 (d, J=8.1 Hz,
1H), 7.56 (d, J=4.4 Hz, 1H), 3.99 (d, J=12.0 Hz, 2H), 3.09 (d,
J=12.4 Hz, 3H), 1.94 (d, J=11.6 Hz, 2H), 1.56 (d, J=11.1 Hz, 2H).
ESI MS m/z=406.1 (M+1)
Example 243
1-(3-methyl-6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-y-
l)piperidin-4-amine 243
[0363] In a microwave reaction vial was charged with tert-butyl
1-(3-chloro-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-p-
yrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-4-ylcarbamate
from Example 241 (72.1 mg, 0.113 mmol), Methyl boronic acid (34.0
mg, 0.567 mmol), 1,1'-Bis(diphenylphosphino)ferrocenepalladium (II)
chloride (9.25 mg, 0.0113 mmol), 1.00 M of Potassium acetate in
Water (0.17 mL, 0.17 mmol), 1.00 M of Sodium carbonate in Water
(0.17 mL, 0.17 mmol), and Acetonitrile (3 mL). The reaction mixture
was heated under microwave at 150.degree. C. for 3 minutes. Another
5 equivalents of Methyl boronic acid was added and continue heated
under microwave at 150.degree. C. for 3 minutes. The same procedure
was repeated 2 more times. The mixture was concentrated to afford
crude tert-butyl
1-(3-methyl-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-p-
yrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-4-ylcarbamate,
which was dissolved in 1,4-Dioxane (5 mL) and treated with 4.0 M of
Hydrogen chloride in 1,4-Dioxane (5 mL) overnight at room
temperature. The mixture was then concentrated, and the residue was
purified by reverse phase HPLC to afford 243 as an off-white solid
(14.0 mg, 32%). 1H NMR (400 MHz, DMSO) .delta. 9.24 (d, J=17.9 Hz,
2H), 9.07 (s, 1H), 8.61 (s, 1H), 8.43 (d, J=7.8 Hz, 1H), 8.38 (s,
1H), 7.76 (d, J=7.6 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.56 (d, J=4.6
Hz, 1H), 3.73 (d, J=11.9 Hz, 2H), 3.13 (s, 1H), 3.01 (d, J=11.6 Hz,
2H), 2.32 (s, 3H), 2.02 (d, J=12.0 Hz, 2H), 1.68 (d, J=11.1 Hz,
2H). ESI MS m/z=386.2 (M+1)
Example 246
(R)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyri-
din-2-yl)azepan-4-amine 246
Step 1: benzyl
(4R)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-p-
yrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-ylcarbamate
##STR00496##
[0365] Following the procedure of Example 189,
3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-py-
ran-2-yl)-1H-pyrazolo[3,4-c]pyridine and (R)-benzyl
azepan-4-ylcarbamate were reacted to give benzyl
(4R)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-p-
yrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-ylcarbamate as a
solid (90.5%). LC/MS: m/z 607.3 [M+1].
Step 2:
(4R)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-y-
l)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-amine
[0366] In a 5-mL high-pressure vial was placed benzyl
(4R)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-p-
yrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-ylcarbamate (110.0
mg, 0.18 mmol), 1,4-cyclohexadiene (102 .mu.L, 1.09 mmol) in
ethanol (8.3). 10% Pd on C (11.0 mg) was added, and the reaction
mixture was vacuum purged with N.sub.2 3.times.. The vial was
sealed and the reaction mixture was stirred at 100.degree. C. After
2 h additional 10% Pd on C (11.0 mg) and 1,4-cyclohexadiene (102
.mu.L) were added. The vial was resealed and the reaction mixture
was stirred at 100.degree. C. for 14 h. The cooled reaction was
filtered reaction through a pad of Celite.RTM., and the pad was
rinsed with EtOAc (3.times.5 mL), MeOH (3.times.5 mL), DCM
(3.times.5 mL), and a final rinse of EtOAc (3.times.5 mL). The
filtrate was concentrated under reduced pressure, and the crude
product was purified using flash chromatography (Si-PPC gradient
elution, solvent: 0-80% MeOH in EtOAc+1% Et.sub.3N) to give
(4R)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-p-
yrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-amine as a solid
(61.1 mg, 71.3%). LC/MS: m/z 473.3 [M+1].
Step 3
[0367] Following the procedure of Example 189,
(4R)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-p-
yrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-amine was
deprotected to give 246 as a white solid (52.1%). .sup.1H NMR (400
MHz, DMSO) .delta. 9.03 (d, J=1.1 Hz, 1H), 8.55 (d, J=1.1 Hz, 1H),
8.11 (s, 1H), 7.84 (s, 1H), 7.66-7.56 (m, 1H), 7.38 (d, J=7.3 Hz,
1H), 6.62 (d, J=8.5 Hz, 1H), 3.97 (m, 1H), 3.91 (s, 3H), 3.86-3.76
(m, 1H), 3.76-3.58 (m, 3H), 2.93 (t, 1H), 2.14-1.95 (m, 2H),
1.86-1.60 (m, 3H), 1.42 (m, 1H); 2 protons not seen. LC/MS: m/z
389.2 [M+1]
Example 247
5-(1-methyl-1H-pyrazol-4-yl)-3-(6-(piperidin-4-yl)pyridin-2-yl)-1H-pyrazol-
o[3,4-c]pyridine 247
Step 1: tert-butyl
4-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazo-
lo[3,4-c]pyridin-3-yl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate
##STR00497##
[0369] In a high-pressure vial was placed
3-(6-chloropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-py-
ran-2-yl)-1H-pyrazolo[3,4-c]pyridine ((84.1 mg, 0.21 mmol),
tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-
-carboxylate (197.5 mg, 0.64 mmol), cesium carbonate (346.979 mg,
1.06494 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloro-methane (1:1) (17.4 mg, 0.021 mmol), and
N,N-Dimethylformamide (2.5 mL). Nitrogen was passed through the
mixture for 15 minutes and the vessel was sealed. The reaction
mixture was stirred at 90.degree. C. under N.sub.2 for 4 days,
cooled to RT, and diluted with EtOAc. The reaction mixture was
filtered through a pad of Celite.RTM.. The organic layer was washed
with water and brine, dried over Na.sub.2SO.sub.4, filtered, and
evaporated in vacuo. The crude product was purified using both
flash chromatography (Si-PPC gradient elution, solvent: 0-20%
methanol in ethyl acetate) and reverse phase HPLC purification to
give tert-butyl
4-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazo-
lo[3,4-c]pyridin-3-yl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate
as an oil (40.4 mg, 35.0%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.12 (s, 1H), 8.72 (s, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.98
(s, 1H), 7.93 (s, 1H), 7.75 (t, J=7.8 Hz, 1H), 7.39 (d, J=7.7 Hz,
1H), 6.79 (s, 1H), 5.87 (dd, J=8.5, 2.0 Hz, 1H), 4.23 (d, J=2.6 Hz,
2H), 4.07-3.96 (m, 1H), 3.98 (s, 3H), 3.85-3.72 (m, 3H), 2.87 (s,
2H), 2.66-2.52 (m, 1H), 2.17 (d, J=9.2 Hz, 2H), 1.90-1.67 (m, 3H),
1.52 (s, 9H). LC/MS: m/z 542.4 [M+1].
Step 2: tert-butyl
4-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazo-
lo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidine-1-carboxylate
##STR00498##
[0371] In a microwave vial was placed tert-butyl
4-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazo-
lo[3,4-c]pyridin-3-yl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate
(40.0 mg, 0.074 mmol), 1,4-cyclohexadiene (69 .mu.L, 0.74 mmol),
and ethanol (3.000 mL). Palladium (4.0 mg, 0.04 mmol; 10% Pd on C)
was added and the reaction mixture was vacuum purged with N.sub.2
3.times., ending with N.sub.2. The vial was capped and the reaction
mixture was subjected to microwave irradiation at 120.degree. C.
for 60 min. Additional 10% palladium on C (4.0 mg) and
cyclohexadiene (69 .mu.L) were added, and the reaction mixture was
resubjected to microwave irradiation 120.degree. C. for 60 minutes.
This process was repeated (2.times.) until no starting material was
detected by LC/MS. The reaction mixture was filtered through a pad
of Celite.RTM.. The pad was rinsed with ethyl acetate (3.times.5
mL), MeOH (3.times.5 mL), DCM (3.times.5 mL), and a final EtOAc
rinse (3.times.5 mL). The combined filtrates were concentrated
under reduced pressure and pumped dry on high-vac to give
tert-butyl
4-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazo-
lo[3,4-c]pyridin-3-yl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate
(27.7 mg, 69.0%). LC/MS: m/z 544.4 [M+1].
Step 3
[0372] Following the procedure as in Example 189, tert-butyl
4-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazo-
lo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidine-1-carboxylate was
deprotected to give 247 as a solid (45.3%). .sup.1H NMR (400 MHz,
DMSO) .delta. 9.06 (d, J=1.2 Hz, 1H), 8.65 (s, 1H), 8.37 (s, 2H),
8.22 (s, 1H), 8.02 (d, J=7.8 Hz, 1H), 7.96 (s, 1H), 7.87 (t, J=7.8
Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 3.92 (s, 3H), 3.36 (broad s, 1H),
3.33 (broad s, 1H), 3.10 (t, 1H), 2.97 (t, 2H), 2.11 (d, 2H), 2.03
(m, 2H). LC/MS: m/z 360.1 [M+1]
Example 248
(S)-1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)aze-
pan-4-amine 248
[0373] To benzyl (4
S)-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]-
pyridin-3-yl)pyridin-2-yl)azepan-4-ylcarbamate (0.100 g, 0.166
mmol) was added 2.0 M Hydrogen chloride in Water (10.0 mL). The
reaction was stirred for 18 h at 100.degree. C. The reaction was
concentrated then submitted to HPLC purification to give 248 (6.9
mg, 11% yield). ESI MS m/z=386.1 (M+1). .sup.1H NMR (500 MHz, DMSO)
.delta. 9.22 (s, 1H), 9.19 (s, 1H), 8.95 (s, 1H), 8.59 (d, J=4.3
Hz, 1H), 8.38 (d, J=7.6 Hz, 1H), 7.61 (t, J=7.7 Hz, 1H), 7.57-7.51
(m, 1H), 7.42 (d, 0.1=7.3 Hz, 1H), 6.61 (d, 0.1=8.3 Hz, 1H),
3.80-3.70 (m, 2H), 3.60-3.55 (m, 2H), 2.95-2.85 (m, 1H), 2.10-1.96
(m, 2H), 1.86-1.56 (m, 3H), 1.40 (m, 1H)
Example 249
(R)-1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)aze-
pan-4-amine 249
[0374] A solution containing
3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-
-pyrazolo[3,4-c]pyridine (0.075 g, 0.20 mmol) and (R)-benzyl
azepan-4-ylcarbamate (0.298 g, 1.20 mmol) in Dimethyl sulfoxide
(1.20 mL) was heated at 95.degree. C. for 18 h. The reaction was
quenched with water and then extracted with EtOAc 2.times.. The
combined organic layer was dried with Na2SO4, filtered and
concentrated. The crude product was dried under high vacuum
overnight to give benzyl
(4R)-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4--
c]pyridin-3-yl)pyridin-2-yl)azepan-4-ylcarbamate which was
dissolved in Methylene chloride (2.56 mL) at -10.degree. C. and
treated with slowly with 1.00 M of Boron tribromide in Methylene
chloride (0.600 mL). The reaction was stirred at RT for 7 h. The
mixture was concentrated. The crude product was diluted in water
and washed with EtOAc. The aqueous layer was basified to pH 11 then
extracted with EtOAc. The combined organic layers was dried Na2SO4,
filtered, and concentrated. The crude product was submitted for
rHPLC to give 249 (21 mg, 27% yield). ESI MS m/z=386.1 (M+1).
.sup.1H NMR (500 MHz, DMSO) .delta. 9.21 (d, J=12.7 Hz, 2H), 8.96
(s, 1H), 8.59 (d, J=3.8 Hz, 1H), 8.38 (d, J=7.6 Hz, 1H), 7.61 (t,
J=7.6 Hz, 1H), 7.58-7.51 (m, 1H), 7.42 (d, J=7.3 Hz, 1H), 6.62 (d,
J=8.2 Hz, 1H), 4.00-3.78 (m, 2H), 3.76-3.57 (m, 2H), 2.89 (s, 1H),
2.00 (d, J=30.7 Hz, 2H), 1.85-1.55 (m, 3H), 1.44-1.31 (m, 1H)
Example 250
2-methyl-1-(4-(5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl-
)-1H-pyrazol-1-yl)propan-2-ol 250
[0375] Following the procedures in Example 172,
2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1--
yl)propan-2-ol and
3-chloro-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyr-
azolo[3,4-c]pyridine were reacted and deprotected to give 250 as a
white solid (40.7% over two steps). .sup.1H NMR (500 MHz, DMSO)
.delta. 13.39 (s, 1H), 8.97 (s, 1H), 8.39 (s, 1H), 8.30 (s, 1H),
8.16 (d, J=10.2 Hz, 2H), 8.10 (s, 1H), 4.78 (s, 1H), 4.13 (s, 2H),
3.90 (s, 3H), 1.13 (s, 6H). LC/MS: m/z 338.1 [M+1]
Example 251
(1s,4s)-N1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl-
)pyridin-2-yl)cyclohexane-1,4-diamine 251
[0376] Following the procedures as described in Example 189,
3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-py-
ran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl
(1s,4s)-4-aminocyclohexylcarbamate were reacted. The product was
deprotected and purified to give 251 as a white solid (41.4% over
two steps). .sup.1H NMR (500 MHz, DMSO) .delta. 9.01 (s, 1H), 8.59
(s, 1H), 8.13 (s, 1H), 7.87 (s, 1H), 7.46 (t, J=7.5 Hz, 1H), 7.29
(d, J=7.0 Hz, 1H), 6.55 (dd, J=14.4, 7.8 Hz, 2H), 4.12 (s, 1H),
3.90 (s, 3H), 3.42 (s, 1H), 2.87 (s, 1H), 1.99-1.39 (m, 9H); 1
proton not seen. LC/MS: m/z 389.2 [M+1]
Example 252
5-(pyridin-3-yl)-3-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-c]pyridine
252
[0377] To a solution of
5-(pyridin-3-yl)-3-(pyrrolidin-1-yl)-1-trityl-1H-pyrazolo[3,4-c]pyridine
(0.120 g, 0.236 mmol) in Methylene chloride (3.030 mL, 47.28 mmol)
was added Triethylsilane (0.151 mL, 0.946 mmol) and Trifluoroacetic
Acid (3.642 mL, 47.28 mmol). The mixture was stirred at RT for 3 h.
The reaction was concentrated. The crude was submitted for HPLC
purification in DMF to give 252 (22.4 mg, 35.7% yield). ESI MS
m/z=266.1 (M+1). .sup.1H NMR (400 MHz, DMSO) .delta. 12.34 (s, 1H),
9.30 (d, J=1.8 Hz, 1H), 8.90 (d, J=0.9 Hz, 1H), 8.53 (dd, J=4.7,
1.5 Hz, 1H), 8.50-8.42 (m, 1H), 8.32 (s, 1H), 7.47 (dd, J=7.9, 4.7
Hz, 1H), 3.63 (t, J=6.5 Hz, 4H), 1.99 (t, J=6.5 Hz, 4H)
Example 253
2-(3-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)aceta-
mide 253
Step 1: Diethyl
2-(3-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)-1-(tetrahydr-
o-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)malonate
##STR00499##
[0379] A mixture of 218 mg (0.40 mmol) of
4-{6-[5-Bromo-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl]-p-
yridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester, 1.22 mL
(8.02 mmol) of Ethyl malonate, 76 mg (0.40 mmol) of copper(I)
iodide, 654 mg (2.006 mmol) of cesium carbonate and 99 mg (0.80
mmol) of picolinic acid in 4.0 ml of 1,4-dioxane was degassed and
then heated for 24 hours at 100.degree. C. The mixture was filtered
and the filtrate concentrated in vacuum. The residue was
partitioned between ethyl acetate and water, the organic extracts
were washed consequently with saturated aqueous NaHCO3, 5% aqueous
citric acid, water, brine, dried over MgSO4 and concentrated. The
residue was purified via silica gel chromatography using a gradient
of ethyl acetate in heptane to afford 117 mg (47%) of Diethyl
2-(3-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)-1-(tetrahydr-
o-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)malonate. ESI MS
m/z 623.3 (M+1).
Step 2:
2-(3-(6-(4-(tertButoxycarbonyl)piperazin-1-yl)pyridin-2-yl)-1-(tet-
rahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)acetic
acid
##STR00500##
[0381] A mixture of diethyl
2-(3-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)-1-(tetrahydr-
o-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)malonate (117 mg
(0.188 mmol) and 0.5 ml of 1 M aqueous solution of LiOH in 6 ml of
methanol/THF mixture (2:1) was heated at 60.degree. C. for 1 hour.
The mixture was acidified with 1 N aqueous HCl to pH<1 and
stirred for 20 min. The mixture was concentrated, the residue
partitioned between ethyl acetate and water. The pH of the mixture
was adjusted to 4 by careful addition of saturated aqueous sodium
bicarbonate. The organic extracts were washed with brine, dried
over MgSO4 and concentrated to afford
2-(3-(6-(4-(tertButoxycarbonyl)piperazin-1-yl)pyridin-2-yl)-1-(tetrahydro-
-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)acetic acid (68 mg,
32% over two steps. ESI MS m/z 523.4 (M+1).
Step 3
[0382] Following the procedure of Example 229,
2-(3-(6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)-1-(tetrahydr-
o-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)acetic acid was
converted into amide which was deprotected by Example 225. The
mixture was purified via reverse phase HPLC using a gradient of
MeOH in water with 0.1% NH.sub.4OH to afford 7.3 mg (5.4%%) of 253
over four steps. ESI MS m/z 338.1 (M+1). 1H NMR (500 MHz, DMSO):
13.70 (s, 1H), 8.97 (s, 1H), 8.33 (s, 1H), 7.64 (t, J=7.8 Hz, 1H),
7.52 (s, 1H), 7.44 (d, J=7.2 Hz, 1H), 6.96 (s, 1H), 6.80 (d, J=8.3
Hz, 1H), 3.70 (s, 2H), 3.54 (s, 4H), 2.87 (s, 4H)
Example 254
1-methyl-3-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)imidazolidin-2-
-one 254
[0383] A solution of
1-methyl-3-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-
-c]pyridin-3-yl)imidazolidin-2-one (0.140 g, 0.371 mmol) in 4.00 M
of Hydrogen chloride in 1,4-Dioxane (3.00 mL) and 1,4-Dioxane (3.00
mL, 38.4 mmol) was stirred at RT for 18 h. The reaction was
concentrated. The crude product was submitted HPLC to give 254
(16.9 mg, 15.4% yield). ESI MS m/z=295.1 (M+1). .sup.1H NMR (400
MHz, DMSO) .delta. 9.18 (s, 1H), 9.04 (s, 1H), 8.82 (s, 1H), 8.56
(d, J=4.3 Hz, 1H), 8.32 (d, J=8.0 Hz, 1H), 7.50 (dd, J=7.9, 4.7 Hz,
1H), 4.01-3.93 (m, 2H), 3.64-3.53 (m, 2H), 2.86 (s, 3H)
Example 255
3-(5-chloro-6-(4-methylpiperazin-1-yl)pyridin-2-yl)-5-(pyridin-3-yl)-1H-py-
razolo[3,4-c]pyridine 255
[0384] Following the procedures as described in Example 241 and
starting with 1-methylpiperazine, 255 was obtained as an off-white
solid (11.0 mg, 29%) over two steps. 1H NMR (400 MHz, DMSO) .delta.
9.30-9.20 (m, 2H), 8.97 (s, 1H), 8.61 (d, J=4.7 Hz, 1H), 8.41 (d,
J=8.0 Hz, 1H), 7.91 (d, J=8.1 Hz, 1H), 7.79 (d, J=8.1 Hz, 1H), 7.56
(dd, J=8.0, 4.7 Hz, 1H), 3.54 (s, 4H), 2.58 (s, 4H), 2.29 (s, 3H);
ESI MS m/z=406.1 (M+1)
Example 256
3,5-di(pyridin-2-yl)-1H-pyrazolo[3,4-c]pyridine 256
[0385]
3-(Pyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-p-
yrazolo[3,4-c]pyridine (67.6 mg, 0.189 mmol) in 4.0 M of Hydrogen
chloride in 1,4-Dioxane (5 mL) and Methanol (5 mL, 100 mmol) was
stirred overnight at room temperature. The mixture was then
concentrated, and the residue was purified by reverse phase HPLC to
afford 256 as an off-white solid (20.8 mg, 40%). 1H NMR (400 MHz,
DMSO) .delta. 14.04 (s, 1H), 9.50 (s, 1H), 9.19 (d, J=0.9 Hz, 1H),
8.84 (d, J=4.4 Hz, 1H), 8.72 (d, J=4.0 Hz, 1H), 8.45 (d, J=8.0 Hz,
1H), 8.23 (d, J=8.0 Hz, 1H), 7.95 (qd, J=7.6, 1.7 Hz, 2H),
7.46-7.38 (m, 2H); ESI MS m/z=274.1 (M+1)
Example 257
3-(5-methyl-6-(4-methylpiperazin-1-yl)pyridin-2-yl)-5-(pyridin-3-yl)-1H-py-
razolo[3,4-c]pyridine 257
[0386] Following the procedures as described in Example 241 and
starting with 1-methylpiperazine, 257 was obtained as an off-white
solid (6.8 mg, 19%) over two steps. 1H NMR (400 MHz, DMSO) .delta.
9.25 (s, 1H), 9.21 (s, 1H), 9.07 (s, 1H), 8.61 (d, J=4.6 Hz, 1H),
8.41 (d, J=8.0 Hz, 1H), 8.16 (s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.65
(d, J=7.7 Hz, 1H), 7.56 (dd, J=7.9, 4.8 Hz, 1H), 2.60 (s, 4H), 2.31
(d, J=3.7 Hz, 6H); ESI MS m/z=386.2 (M+1)
Example 258
1-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyrrolidin-2-one
258
[0387] Following the procedures of Example 254,
1-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridi-
n-3-yl)pyrrolidin-2-one was converted to 258. ESI MS m/z=280.1
(M+1). .sup.1H NMR (400 MHz, DMSO) .delta. 9.20 (d, J=1.9 Hz, 1H),
9.09 (d, J=1.0 Hz, 1H), 8.66 (d, J=1.0 Hz, 1H), 8.57 (dd, J=4.7,
1.5 Hz, 1H), 8.37-8.31 (m, 1H), 7.51 (dd, 0.1=7.9, 4.8 Hz, 1H),
4.02 (t, 0.1=7.1 Hz, 2H), 2.60 (t, 0.1=8.0 Hz, 2H), 2.27-2.15 (m,
2H)
Example 259
1-methyl-4-(3-phenyl-1H-pyrazolo[3,4-c]pyridin-5-yl)-1H-pyrrol-2(5H)-one
259
Step 1:
4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-
-5-yl)furan-2(5H)-one
##STR00501##
[0389] A high-pressure reaction vessel was charged with
5-bromo-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine
(400.0 mg, 1.12 mmol), bis(triphenylphosphine)palladium(II)
chloride (79.0 mg, 0.11 mmol), and anhydrous toluene (8.0 mL).
Tributylstannanyl-5H-furan-2-one (437.5 mg, 1.17 mmol) was added,
and the reaction mixture was vacuum-purged and back filled with
nitrogen (3.times.). The vessel was sealed, and the reaction
mixture was stirred at 110.degree. C. for 3 days. The reaction was
cooled to RT and slowly poured into saturated aqueous sodium
bicarbonate solution (30 mL). The resultant mixture was extracted
with ethyl acetate (3.times.75 mL). The combined organic layers
were dried over Na.sub.2SO.sub.4, filtered, and concentrated under
reduced pressure. The crude product was purified using flash column
chromatography (Si-PPC gradient elution, solvent: 0-100% ethyl
acetate in heptanes) to give
4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)f-
uran-2(5H)-one as white solid (130.0 mg, 32.2%). LC/MS: m/z 362.3
[M+1].
Step 2:
1-methyl-5-(methylamino)-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)--
1H-pyrazolo[3,4-c]pyridin-5-yl)pyrrolidin-2-one
##STR00502##
[0391] A high-pressure reaction vessel was charged with
4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)f-
uran-2(5H)-onc (120.0 mg, 0.33 mmol) and 2M methylamine in methanol
(10 mL). The vessel was sealed and the heterogeneous reaction
mixture was stirred at 90.degree. C. for 17 h. The resultant
reaction mixture was cooled to RT. Volatile solvent was evaporated
in vacuo to afford an oil. The oil was taken up in 1:1 v/v
DCM-ether (.about.10 mL). Heptane was slowly added until an orange
solid precipitated out and the precipitate was filtered off. The
filtrate was evaporated in vacuo and dried on high-vacuum pump to
give
1-methyl-5-(methylamino)-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyra-
zolo[3,4-c]pyridin-5-yl)pyrrolidin-2-one (104.8 mg, 77.8%) as a
foam. .sup.1H NMR 1H NMR (400 MHz, CDCl.sub.3) .delta. 9.16 (d,
J=8.2 Hz, 1H), 7.94 (d, J=7.6 Hz, 2H), 7.75 (s, 1H), 7.52 (t, J=7.5
Hz, 2H), 7.43 (t, J=7.3 Hz, 1H), 5.90-5.83 (m, 1H), 4.66 (dd,
J=5.4, 2.0 Hz, 1H), 4.09-4.01 (m, 1H), 3.87-3.76 (m, 1H), 3.59-3.52
(m, 1H), 2.88 (s, 3H), 2.64-2.52 (m, 1H), 2.40 (s, 3H), 2.20 (d,
J=14.8 Hz, 2H), 1.91-1.68 (m, 6H). LC/MS: m/z 406.3 [M+1].
Step 3
[0392] A mixture of
1-methyl-5-(methylamino)-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyra-
zolo[3,4-c]pyridin-5-yl)pyrrolidin-2-one (34.3 mg, 0.084 mmol) and
trifluoroacetic acid (3 mL) in a sealed high-pressure tube was
stirred at 105.degree. C. for 3 days. The reaction was cooled to RT
and trifluoroacetic acid was removed via rotary evaporator. The
resultant oil was diluted with ethyl acetate (30 mL). The organic
layer was washed with aqueous saturated sodium bicarbonate solution
(2.times.), water and brine, dried over Na.sub.2SO.sub.4, filtered,
and evaporated in vacuo. The crude product was purified by reverse
phase HPLC to give 259 as white solid (4.0 mg, 16.3%). .sup.1H NMR
(400 MHz, DMSO) .delta. 9.13 (s, 1H), 8.43 (s, 1H), 8.11 (d, J=7.5
Hz, 2H), 7.56 (t, J=7.6 Hz, 2H), 7.47 (d, J=7.3 Hz, 1H), 6.82 (s,
1H), 6.68 (s, 1H), 4.61 (s, 2H), 2.99 (s, 3H). LC/MS: m/z 291.0
[M+1]
Example 260
1-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)piperidin-2-one
260
[0393] Following the procedures of Example 254,
1-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridi-
n-3-yl)piperidin-2-one was converted to 260. ESI MS m/z=294.1
(M+1)
Example 261
3-(6-(piperidin-1-yl)pyridin-2-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyri-
dine 261
[0394] Following the procedures of Example 271, and starting with
3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)me-
thyl)-1H-pyrazolo[3,4-c]pyridine from Example 279, 261 was obtained
as a yellow solid (20 mg, 32%) over two steps. .sup.1H NMR (400
MHz, DMSO) .delta. 9.22 (s, 2H), 8.97 (s, 1H), 8.60 (s, 1H), 8.38
(d, 1H, J=6, 4 Hz), 7.67-7.64 (t, 1H, J=6, 4 Hz), 7.57-7.54 (m,
1H), 7.45 (d, 1H, 0.1=6, 4 Hz), 6.87 (d, 1H, 0.1=6, 8 Hz), 3.73 (s,
4H), 1.69 (s, 6H). ESI MS m/z=356.4 (M+1)
Example 262
1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin--
2-yl)piperidin-3-ol 262
[0395] Following the procedures as described in Example 189,
3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-py-
ran-2-yl)-1H-pyrazolo[3,4-c]pyridine and piperidin-3-ol were
reacted. The product was deprotected and purified to give 262 as a
white solid (62.8% over two steps). .sup.1H NMR .delta. 13.68
(broad s, 1H), 9.03 (s, 1H), 8.60 (s, 1H), 8.24 (s, 1H), 7.96 (s,
1H), 7.67-7.58 (m, 1H), 7.42 (d, J=7.4 Hz, 1H), 6.83 (d, J=8.5 Hz,
1H), 5.04 (d, J=5.1 Hz, 1H), 4.59-4.49 (m, 1H), 4.08 (d, J=13.1 Hz,
1H), 3.89 (s, 3H), 3.65 (dt, J=14.0, 4.8 Hz, 1H), 3.05 (dd, J=17.1,
6.8 Hz, 1H), 2.91 (dd, J=12.4, 9.4 Hz, 1H), 2.07-1.97 (m, 1H),
1.91-1.78 (m, 1H), 1.65-1.42 (m, 2H). LC/MS: m/z 376.1 [M+1]
Example 263
1-methyl-4-(3-phenyl-1H-pyrazolo[3,4-c]pyridin-5-yl)pyrrolidin-2-one
263
[0396] In a high-pressure vessel was placed
1-methyl-5-(methylamino)-4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyra-
zolo[3,4-c]pyridin-5-yl)pyrrolidin-2-one 259 (70.0 mg, 0.17 mmol)
and trifluoroacetic acid (5 mL). The vessel was sealed and the
reaction mixture was stirred at 105.degree. C. for 20 h. The
reaction mixture was cooled to RT, and triethylsilane (0.50 mL) was
added. The vessel was resealed, and the reaction mixture was
stirred at 75.degree. C. After 2 h, more triethylsilane (0.5 mL)
was added at RT, and the reaction mixture was stirred in a sealed
vessel at 95.degree. C. for 17 h. Volatile solvent was evaporated
in vacuo. The resultant crude oil was dissolved in DMF (2 mL).
Black insoluble material was filtered and rinsed well with methanol
(2.times.2 mL). The combined filtrates were evaporated in vacuo and
the crude product was purified by reverse phase HPLC to give 263 as
a white solid (12.7 mg, 25.2%). .sup.1H NMR (400 MHz, DMSO) .delta.
13.37 (broad s, 1H), 9.08 (s, 1H), 8.04 (d, J=7.4 Hz, 2H), 7.98 (s,
1H), 7.54 (t, J=7.6 Hz, 2H), 7.44 (d, J=7.4 Hz, 1H), 3.98-3.85 (m,
1H), 3.75 (t, J=9.0 Hz, 1H), 3.53 (dd, J=9.3, 7.2 Hz, 1H), 2.78 (s,
3H), 2.66 (dd, J=8.8, 2.9 Hz, 2H). LC/MS: m/z 293.1 [M+1]
Example 264
(R)-5-(1-methyl-1H-pyrazol-4-yl)-3-(6-(piperidin-3-yloxy)pyridin-2-yl)-1H--
pyrazolo[3,4-c]pyridine 264
Step 1: (3R)-tert-butyl
3-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazo-
lo[3,4-c]pyridin-3-yl)pyridin-2-yloxy)piperidine-1-carboxylate
##STR00503##
[0398] To (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate (61.2
mg, 0.30 mmol) in anhydrous DMF (3 mL) was added sodium hydride
(40.5 mg, 1.01 mmol, 60% in mineral oil), and the reaction mixture
was stirred at 60.degree. C. under N.sub.2 for 1 h. A solution of
3-(6-chloropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-py-
ran-2-yl)-1H-pyrazolo[3,4-c]pyridine (40.0 mg, 0.10 mmol) in
anhydrous DMF (=1.0 mL) was then added, and the reaction mixture
was stirred at 90.degree. C. under N.sub.2 for 16 h. The reaction
mixture was quenched with aqueous saturated NH.sub.4Cl solution and
was extracted with ethyl acetate (3.times.). The combined organic
layers were dried over Na.sub.2SO.sub.4, filtered, and evaporated
in vacuo. The crude product was purified using flash chromatography
(Si-PPC gradient elution, solvent: 0-60% MeOH/EA) to give
(3R)-tert-butyl
3-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazo-
lo[3,4-c]pyridin-3-yl)pyridin-2-yloxy)piperidine-1-carboxylate as a
foam (15.8 mg, 27.9%). LC/MS: m/z 560.4 [M+1].
Step 2
[0399] Following the procedure as in Example 189, (3R)-tert-butyl
3-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyra-z-
olo[3,4-c]pyridin-3-yl)pyridin-2-yloxy)piperidine-1-carboxylate was
deprotected to give 264 as a solid (19.1%). .sup.1H NMR (400 MHz,
MeOD) .delta. 8.98 (s, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 8.12 (s,
1H), 7.98 (s, 1H), 7.90-7.80 (m, 2H), 6.90 (d, J=7.6 Hz, 1H), 5.68
(s, 1H), 3.99 (s, 3H), 3.54 (dd, J=13.0, 3.9 Hz, 1H), 3.48-3.42 (m,
1H), 3.29-3.22 (m, 1H), 3.20-3.09 (m, 1H), 2.33-2.23 (m, 1H),
2.19-2.06 (m, 2H), 1.89-1.77 (m, 1H); 1 proton not seen. LC/MS: m/z
376.1 [M+1]
Example 265
(S)-1-(3-chloro-6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-
-2-yl)piperidin-3-amine 265
[0400] Following the procedures as described in Example 241 and
starting with (S)-tert-butyl piperidin-3-ylcarbamate, 265 was
obtained as an off-white solid (8.4 mg, 25%) over two steps. 1H NMR
(400 MHz, DMSO) .delta. 9.31 (s, 1H), 9.23 (s, 1H), 9.03 (s, 1H),
8.60 (d, J=4.4 Hz, 1H), 8.49-8.42 (m, 1H), 7.90 (d, J=8.1 Hz, 1H),
7.78 (d, J=8.1 Hz, 1H), 7.53 (dd, J=7.9, 4.8 Hz, 1H), 6.62 (s, 1H),
3.90 (dd, J=33.6, 11.5 Hz, 2H), 2.91 (dd, J=13.2, 7.5 Hz, 2H),
2.85-2.75 (m, 1H), 1.96 (d, J=12.4 Hz, 1H), 1.83 (s, 1H), 1.74 (d,
J=9.8 Hz, 2H), 1.36-1.24 (m, 1H); ESI MS m/z=406.2 (M+1)
Example 266
(R)-1-(3-chloro-6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-
-2-yl)piperidin-3-amine 266
[0401] Following the procedures as described in Example 241 and
starting with (R)-tert-butyl piperidin-3-ylcarbamate, 266 was
obtained as an off-white solid (55.1 mg, 58%) over two steps. 1H
NMR (400 MHz, DMSO) .delta. 9.31 (d, J=2.1 Hz, 1H), 9.22 (s, 1H),
9.03 (s, 1H), 8.59 (dd, J=4.7, 1.4 Hz, 1H), 8.48-8.43 (m, 1H), 7.89
(d, J=8.1 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.52 (dd, J=8.0, 4.8 Hz,
1H), 3.94 (d, J=9.1 Hz, 1H), 3.87 (d, J=12.1 Hz, 1H), 2.88 (dd,
J=17.0, 6.1 Hz, 2H), 2.82-2.73 (m, 1H), 1.95 (d, J=12.7 Hz, 1H),
1.89-1.72 (m, 2H), 1.31-1.22 (m, 1H); ESI MS m/z=406.2 (M+1)
Example 267
4-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)morphol-
ine 267
[0402] Following the procedures of Example 271, and starting with
3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)me-
thyl)-1H-pyrazolo[3,4-c]pyridine, 267 was obtained as a yellow
solid (20 mg, 32%) over two steps. .sup.1H NMR (400 MHz, DMSO)
.delta. 9.25 (s, 1H), 9.22 (s, 1H), 8.93 (s, 1H), 8.60-9.59 (m,
1H), 8.39-8.37 (m, 1H), 7.74-7.71 (t, 1H), 7.57-7.54 (m, 2H), 6.91
(d, 1H, J=6, 8 Hz), 3.83-3.80 (m, 4H), 3.67-3.65 (m, 4H). ESI MS
m/z=358.4 (M+1)
Example 268
(S)-1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pyr-
rolidin-3-amine 268
[0403] Following the procedures of Example 271, and starting with
3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)me-
thyl)-1H-pyrazolo[3,4-c]pyridine, 268 was obtained as a yellow
solid (58 mg, 46%) over two steps. .sup.1H NMR (400 MHz, DMSO)
.delta. 9.29 (s, 1H), 9.23 (s, 1H), 9.06 (s, 1H), 8.62 (s, 1H),
8.44 (d, J=6.0, 1H), 7.69 (t, J=6.4, 1 H), 7.59-7.57 (m, 1H), 7.49
(d, J=5.6, 1H), 6.54 (d, J=6.4, 1H), 3.98 (s, 1H), 3.88-3.68 (m,
4H), 2.40-2.35 (m, 1H), 2.17-2.13 (m, 1H). ESI MS m/z=358.1
(M+1)
Example 269
(S)-(1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)py-
rrolidin-3-yl)methanamine 269
[0404] Following the procedures of Example 271, and starting with
(S)-pyrrolidin-3-ylmethanamine, 269 was obtained as a yellow solid
(30 mg, 35%) over three steps. .sup.1H NMR (400 MHz, DMSO) .delta.
9.27 (s, 1H), 9.20 (s, 1H), 9.13 (s, 1H), 8.59 (s, 1H), 8.43-8.41
(m, 1H), 7.64-7.61 (s, 1H), 7.54-7.52 (m, 1H), 7.42-7.40 (m, 1H),
6.46-6.45 (d, j=6.4, 1H), 3.81-3.80 (m, 2H), 3.65-3.64 (m, 2H),
3.14-3.13 (m, 2H), 2.18-2.13 (m, 2H), 1.83-1.81 (m, 2H), 1.22 (s,
1H). ESI MS m/z=374 (M+1)
Example 270
(R)-(1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)py-
rrolidin-3-yl)methanamine 270
[0405] Following the procedures of Example 271, and starting with
(R)-pyrrolidin-3-ylmethanamine, 270 was obtained as a yellow solid
(34 mg, 36%) over three steps. .sup.1H NMR (400 MHz, DMSO) .delta.
9.28 (s, 1H), 9.21 (s, 1H), 9.15 (s, 1H), 8.60 (s, 1H), 8.42-8.41
(m, 1H), 7.63-7.60 (s, 1H), 7.54-7.52 (m, 1H), 7.42-7.40 (m, 1H),
6.46-6.45 (d, j=6.4, 1H), 3.81-3.80 (m, 2H), 3.65-3.64 (m, 2H),
3.14-3.13 (m, 2H), 2.19-2.17 (m, 2H), 1.82-1.78 (m, 2H), 1.24 (s,
1H). ESI MS m/z=374 (M+1)
Example 271
(R)-1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pip-
eridin-3-ol 271
Step 1:
3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)et-
hoxy)methyl)-1H-pyrazolo[3,4-c]pyridine
##STR00504##
[0407] To a mixture of
3-iodo-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[-
3,4-c]pyridine (GCP-P3-205-1) (200 mg, 0.44 mmol) and
2-fluoro-6-(tributylstannyl)pyridine (206 mg, 0.53 mmol) in 3 mL
DMF, was added TEA 1 mL, LiCl (56 mg, 1.32 mmol) and CuI (84 mg,
0.44 mmol), and Pd(PPh.sub.3).sub.4 (254 mg, 0.22 mmol). The
reaction mixture was heated at 120.degree. C. under microwave
irradiation for 1 h, and the reaction was monitored by LCMS. Upon
completion, the reaction mixture was extracted with 100 mL EtOAc,
washed with 50 mL brine, and dried. The solvent was distilled off
and the crude material was purified via flash chromatography,
eluting with 5% to 30% ethyl acetate in heptane to afford
3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)me-
thyl)-1H-pyrazolo[3,4-c]pyridine as a yellow solid (148 mg, 80%).
ESI MS m/z=421.1 (M+1).
Step 2:
(R)-1-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-
-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-3-ol
##STR00505##
[0409] To a mixture of
3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)me-
thyl)-1H-pyrazolo[3,4-c]pyridine (200 mg, 0.5 mmol) and
(R)-piperidin-3-ol (100 mg, 1.0 mmol) in EtOH 5 mL, was added DIPEA
5 mL. The reaction mixture was heated at 120.degree. C. for 15 h,
and the reaction was monitored by LCMS. Upon completion of the
reaction, the solvent was distilled off and the crude material was
purified via flash chromatography, eluting with 5% to 30%
heptane/ethyl acetate to afford
(R)-1-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazo-
lo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-3-ol as a yellow oil,
(163 mg, 65%). ESI MS m/z=502.2 (M+1).
Step 3
[0410] To a solution of
(R)-1-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazo-
lo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-3-ol (60 mg, 0.12
mmol) in dioxane 5 mL, was added 10% HCl (1 mL). The reaction
mixture was heated at 70.degree. C. for 2 h, and the reaction was
monitored by LCMS. Upon completion of the reaction, the solvent was
distilled off and the crude material was purified via reverse phase
prep-HPLC eluting with 40% to 80% MeOH in aqueous 0.1% NH.sub.4OH
to afford 271 as a yellow solid (20 mg, 45%). .sup.1H NMR (400 MHz,
DMSO) .delta. 9.34-9.28 (m, 1H), 9.21 (s, 1H), 8.62-8.58 (m, 1H),
8.45 (d, J=6, 1H), 7.67-7.64 (m, 1H), 7.54-7.50 (m, 1H), 7.45-7.44
(m, 1H), 6.87-6.85 (m, 1H), 4.96 (s, 1H), 4.36-4.34 (m, 1H),
4.15-4.12 (m, 1H), 3.63 (s, 1H), 3.16-3.12 (m, 1H), 3.01-2.97 (m,
1H), 1.99-1.97 (m, 1H), 1.85-1.83 (m, 1H), 1.60-1.56 (m, 1H),
1.52-1.45 (m, 1H). ESI MS m/z=373.7 (M+1)
Example 272
1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperid-
in-4-ol 272
[0411] Following the procedures of Example 271, and starting with
3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)me-
thyl)-1H-pyrazolo[3,4-c]pyridine, 272 was obtained as a yellow
solid (20 mg, 30%) over two steps. .sup.1H NMR (400 MHz, DMSO)
.delta. 9.22-9.20 (m, 2H), 8.94 (s, 1H), 8.60-8.59 (m, 1H),
8.39-8.38 (m, 1H), 7.67-7.64 (m, 1H), 7.56-7.53 (m, 1H), 7.47-7.44
(m, 1H), 6.90-6.89 (m, 1H), 4.77-4.76 (m, 1H), 4.22-4.19 (m, 2H),
3.80-3.79 (m, 1H), 3.42-3.39 (m, 1H), 1.91-1.89 (m, 2H), 1.51-1.49
(m, 2H). ESI MS m/z=373.7 (M+1)
Example 273
3-(6-(4,4'-bipiperidin-1-yl)pyridin-2-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-
-c]pyridine 273
[0412] Following the procedures of Example 143, and starting with
3-(6-Fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-
-pyrazolo[3,4-c]pyridine and 4,4'-bipiperidine, 273 was obtained
and purified via reverse phase HPLC using a gradient of MeCN in
water with 0.1% HCOOH to afford 25 mg (20%) over two steps. ESI MS
m/z 440.2 (M+1). 1H NMR (400 MHz, DMSO): 9.23 (s, 1H), 8.97 (s,
1H), 8.61 (s, 1H), 8.39 (s, 1H), 7.67 (t, J=7.9 Hz, 1H), 7.55 (s,
1H), 7.46 (d, J=7.3 Hz, 1H), 6.89 (d, J=8.2 Hz, 1H), 4.54 (d,
J=11.1 Hz, 2H), 2.97 (s, 2H), 2.66 (s, 2H), 1.88-1.71 (m, 4H), 1.46
(s, 1H), 1.31 (s, 5H)
Example 274
3-(6-fluoro-5-methylpyridin-2-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyrid-
ine 274
[0413] A microwave reaction vial was charged with
3-(5-chloro-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)-
ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (387.1 mg, 0.8489 mmol),
methyl boronic acid (254.1 mg, 4.245 mmol),
1,1'-Bis(diphenylphosphino)ferrocenepalladium (II) chloride (69.3
mg, 0.085 mmol), 1.00 M of Potassium acetate in Water (1.27 mL,
1.27 mmol), 1.00 M of Sodium carbonate in Water (1.27 mL, 1.27
mmol), and Acetonitrile (10 mL). The reaction mixture was heated
under microwave at 150.degree. C. for 5 minutes. Added another 5
equivalences of Methyl boronic acid and continue heated under
microwave at 150.degree. C. for 3 minutes. The same procedure was
repeated one more times. The mixture was concentrated, and the
residue was purified on silica eluted with 0 to 100% EtOAc in
Heptane to afford
3-(6-fluoro-5-methylpyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)-
ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (311.7 mg, 84%).
[0414]
3-(6-Fluoro-5-methylpyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethyl-
silyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine was dissolved in
trifluoroacetic acid (5 mL) and methylene chloride (5 mL). To the
solution was added trifluoromethanesulfonic acid (104.2 uL, 1.18
mmol) and triethylsilane (18.1 uL, 1.18 mmol). The resulting
mixture was stirred overnight at room temperature. The mixture was
then concentrated, and the residue was purified by reverse phase
HPLC to afford 274 as an off-white solid (7.8 mg, 11%). 1H NMR (400
MHz, DMSO) .delta. 9.29-9.21 (m, 2H), 8.81 (s, 1H), 8.62 (dd,
J=4.7, 1.4 Hz, 1H), 8.42 (dt, J=8.0, 1.9 Hz, 1H), 8.06 (dd, J=7.6,
1.6 Hz, 1H), 8.01-7.95 (m, 1H), 7.55 (dd, J=8.0, 4.8 Hz, 1H), 2.34
(s, 3H); ESI MS m/z=306.1 (M+1)
Example 275
3-(5-methylpyridin-2-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine
275
Step 1:
5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(trimethyl-
stannyl)-1H-pyrazolo[3,4-c]pyridine
##STR00506##
[0416] To a mixture of
3-iodo-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[-
3,4-c]pyridine (200 mg, 0.44 mmol) and
1,1,1,2,2,2-hexamethyldistannane (159 mg, 0.48 mmol) in 10 mL THF,
was added LiCl (112 mg, 2.64 mmol) and Pd(PPh.sub.3)Cl.sub.2 (16
mg, 0.02 mmol). The reaction mixture was heated at 80.degree. C.
under argon for 1 h, and the reaction was monitored by LCMS. Upon
completion of the reaction, the mixture was evaporated to dryness.
The residue was purified via flash chromatography eluting with
CH.sub.2Cl.sub.2/CH.sub.3OH (9:1) to afford
5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(trimethylstannyl-
)-1H-pyrazolo[3,4-c]pyridine as a clear oil (188 mg, 87%). ESI MS
m/z=490.1 (M+1).
Step 2:
3-(5-methylpyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)et-
hoxy)methyl)-1H-pyrazolo[3,4-c]pyridine
##STR00507##
[0418] To a mixture of
5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(trimethylstannyl-
)-1H-pyrazolo[3,4-c]pyridine (250 mg, 0.51 mmol) and
2-bromo-5-methylpyridine (87 mg, 0.51 mmol) in DMF 10 mL, was added
TEA (10 mL), LiCl (64 mg, 1.53 mmol), CuI (97 mg, 0.51 mmol), and
Pd(PPh.sub.3).sub.4 (294 mg, 0.25 mmol). The reaction mixture was
heated at 120.degree. C. under microwave irradiation for 1 h, and
the reaction was monitored by LCMS. Upon completion of the
reaction, the mixture was extracted with 100 mL EtOAc, washed with
50 mL brine, and dried. The solvent was distilled off and the crude
material was purified via flash chromatography, eluting with 33% to
66% ethyl acetate in heptane to afford
3-(5-methylpyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)et-
hoxy)methyl)-1H-pyrazolo[3,4-c]pyridine as an clear oil (115 mg,
54%). ESI MS m/z=417.2 (M+1).
Step 3
[0419] To a solution of
3-(5-methylpyridin-2-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine
(110 mg, 0.26 mmol) in dioxane (5 mL), was added 10% HCl (2 mL).
The reaction mixture was heated at 80.degree. C. for 2 h, and the
reaction was monitored by LCMS. Upon completion of the reaction,
the solvent was distilled off and the crude material was purified
via reverse phase prep-HPLC eluting with 40% to 80% CH.sub.3CN in
aqueous 0.1% NH.sub.4OH solution to afford 275 as a pink solid (32
mg, 42%). .sup.1H NMR (400 MHz, DMSO) .delta. 9.28 (s, 1H), 9.23
(s, 1H), 9.21 (s, 1H), 8.93 (s, 1H), 8.65-8.60 (m, 2H), 8.44-8.43
(m, 1H), 8.11 (d, 1H, J=6, 4 Hz), 7.77 (d, 1H, J=6, 8 Hz),
7.55-7.53 (m, 1H), 3.32 (s, 3H). ESI MS m/z=287.3 (M+1)
Example 276
(R)-1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pyr-
rolidin-3-amine 276
[0420] Following the procedures in Example 271,
3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)me-
thyl)-1H-pyrazolo[3,4-c]pyridine was converted to 276 as a yellow
solid (24 mg, 25%) over two steps. .sup.1H NMR (400 MHz,
DMSO&H.sub.2O) .delta. 9.13 (d, J=8.0, 1H), 9.01 (s, 1H), 8.55
(s, 1H), 8.36 (d, J=6.0, 1H), 7.60-7.54 (m, 2H), 7.35 (d, J=5.6,
1H), 6.42 (d, J=6.8, 1H), 3.72-3.53 (m, 4H), 3.27 (s, 1H), 2.19 (s,
1H), 1.83 (s, 1H). ESI MS m/z=358.1 (M+1)
Example 277
(S)-1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pip-
eridin-3-ol 277
[0421] Following the procedures in Example 271, and starting with
3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)me-
thyl)-1H-pyrazolo[3,4-c]pyridine (GCP-P3-205-3), 277 was obtained
as a yellow solid (20 mg, 25%) over two steps. .sup.1H NMR (400
MHz, DMSO) .delta. 9.34-9.28 (m, 1H), 9.21 (s, 1H), 8.62-8.58 (m,
1H), 8.45 (d, J=6, 1H), 7.67-7.64 (m, 1H), 7.54-7.50 (m, 1H),
7.45-7.44 (m, 1H), 6.87-6.85 (m, 1H), 4.96 (s, 1H), 4.36-4.34 (m,
1H), 4.15-4.12 (m, 1H), 3.63 (s, 1H), 3.16-3.12 (m, 1H), 3.01-2.97
(m, 1H), 1.99-1.97 (m, 1H), 1.85-1.83 (m, 1H), 1.60-1.56 (m, 1H),
1.52-1.45 (m, 1H). ESI MS m/z=373.7 (M+1)
Example 278
(1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperi-
din-4-yl)methanamine 278
Step 1: tert-butyl
(1-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[-
3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-4-yl)methylcarbamate
##STR00508##
[0423] To a mixture of
3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)me-
thyl)-1H-pyrazolo[3,4-c]pyridine from Example 271 (211 mg, 0.5
mmol) and tert-butyl methyl(piperidin-4-yl)carbamate (213 mg, 1.0
mmol) in DMF (5 mL), was added potassium carbonate (138 mg, 1.0
mmol). The reaction mixture was heated at 120.degree. C. for 15 h,
and the reaction was monitored by LCMS. Upon completion of the
reaction, the solvent was distilled off and the crude material was
purified via flash chromatography, eluting with 5% to 30% ethyl
acetate in heptane to afford tert-butyl
(1-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[-
3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-4-yl)methylcarbamate as a
yellow oil (193 mg, 63%). ESI MS m/z=615.34 (M+1).
Step 2
[0424] To a solution of tert-butyl
(1-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[-
3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-4-yl)methylcarbamate (190
mg, 0.31 mmol) in dioxane (5 mL), was added 10% HCl (1 mL). The
reaction mixture was heated at 70.degree. C. for 2 h, and the
reaction was monitored by LCMS. Upon completion of the reaction,
the solvent was distilled off and the crude material was purified
via reverse phase prep-HPLC eluting with 40% to 80% MeOH in aqueous
0.1% NH.sub.4OH solution to afford 278 as a yellow solid (60 mg,
50%). .sup.1H NMR (400 MHz, DMSO) 9.23 (s, 2H), 8.95 (s, 1H),
8.61-8.60 (d, J=2.8, 1H), 8.40-8.38 (m, 1H), 7.68-7.65 (m, 1H),
7.58-7.55 (m, 1H), 7.48-7.46 (m, 1H), 4.96 (s, 1H), 4.53-4.50 (d,
J=10.4, 1H), 3.38-3.36 (m, 3H), 2.69-2.68 (d, J=4, 2H), 188-1.86
(d, J=8.3H), 1.32-1.30 (m, 3H). ESI MS m/z=385.2 (M+1)
Example 279
4-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperaz-
in-2-one 279
Step 1:
4-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyr-
azolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperazin-2-one
##STR00509##
[0426] The mixture of
3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)me-
thyl)-1H-pyrazolo[3,4-c]pyridine from Example 271 (211 mg, 0.5
mmol) and piperazin-2-one (100 mg, 1.0 mmol) in pyridine (5 mL) was
heated at 130.degree. C. for 16 h, and the reaction was monitored
by LCMS. Upon completion of the reaction, the solvent was distilled
off and the crude material was purified via flash chromatography,
eluting with 5% to 30% acetate in heptane to afford
4-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3-
,4-c]pyridin-3-yl)pyridin-2-yl)piperazin-2-one as a yellow oil (76
mg, 30%). ESI MS m/z=501.23 (M+1).
Step 2
[0427] To a solution of
4-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3-
,4-c]pyridin-3-yl)pyridin-2-yl)piperazin-2-one (70 mg, 0.14 mmol)
in dioxane (5 mL), was added 10% HCl 1 mL. The reaction mixture was
stirred at 25.degree. C. for 16 h, and the reaction was monitored
by LCMS. Upon completion of the reaction, the solvent was distilled
off and the crude material was purified via reverse phase prep-HPLC
eluting with 40% to 80% MeOH in aqueous 0.1% NH.sub.4OH solution to
afford 279 as a yellow solid (13 mg, 25%). .sup.1H NMR (400 MHz,
DMSO) .delta. 9.28 (s, 1H), 9.13 (s, 1H), 9.02 (s, 1H), 8.58-8.53
(m, 2H), 7.76-7.73 (t, 1H), 7.64-7.60 (m, 2H), 6.88-6.87 (d, J=6.4,
1H), 4.39 (s, 2H), 3.99-3.98 (t, J=4, 2H). ESI MS m/z=371.15
(M+1)
Example 280
N1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)propan-
e-1,3-diamine 280
[0428] Following the procedures in Example 271,
3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)me-
thyl)-1H-pyrazolo[3,4-c]pyridine and propane-1,3-diamine were
reacted and the product was deprotected to give 280 as a yellow
solid (20 mg, 31%) over two steps. .sup.1H NMR (400 MHz, DMSO)
.delta. 9.30 (s, 1H), 9.22 (s, 1H), 9.03 (s, 1H), 8.60 (s, 1H)
8.43-8.44 (m, 1H), 7.53-7.57 (m, 2H), 7.38-7.40 (m, 1H), 7.03 (s,
1H), 6.53 (d, J=6.4 Hz, 1H), 4.01 (t, J=1.2 Hz, 2H), 2.92 (m, 2H),
2.50 (t, J=1.2 Hz, 2). ESI MS m/z=346 (M+1)
Example 281
3-(3,4-dihydro-2H-pyran-5-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine
281
[0429] In a microwave tube was added
3-iodo-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine from Example 4
(0.32 g, 1 mmol),
2-(5,6-dihydro-4H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(0.31 g, 1.5 mmol), 2 M Na.sub.2CO.sub.3 (2 mmol, 1 mL),
PdCl.sub.2(dppf) (87 mg, 0.1 mmol) and dioxane (8 mL). The
suspension was purged with N.sub.2 and heated under microwave
radiation at 130.degree. C. for 1 hour. It was then cooled to room
temperature. Solvent was removed under reduced pressure. The
residue was purified by SGC (Petrol/EtOAc: 5/1 to 1/1) to give 281
as a yellow solid (97 mg, 35%). 1H NMR (400 MHz, DMSO) .delta. 9.19
(d, J=1.2 Hz, 1H), 9.07 (d, J=0.8 Hz, 1H), 8.53-856 (m, 2H), 8.45
(d, J=0.8 Hz, 1H), 7.71 (s, 1H), 7.47-7.49 (m, 1H), 4.08-4.10 (m,
2H), 2.59-2.61 (m, 2H), 1.98-2.0 (m, 2H). ESI MS m/z=279 (M+1)
Example 282
2-(4-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pipe-
razin-1-yl)ethanol 282
[0430] Following the procedures in Example 271,
3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)me-
thyl)-1H-pyrazolo[3,4-c]pyridine and piperazin-1-yl)ethanol were
reacted and the product was deprotected to give 282 as a yellow
solid (20 mg, 32%) over two steps. .sup.1H NMR (400 MHz, DMSO)
.delta. 9.22 (s, 1H), 8.94 (s, 1H), 8.61 (s, 1H), 8.40-8.38 (m,
1H), 7.70-7.67 (m, 1H), 7.57-7.55 (m, 1H), 7.51-7.49 (m, 1H),
6.90-6.88 (m, 1H), 4.50 (s, 1H), 3.69 (s, 4H), 3.60-3.57 (m, 2H),
2.62 (s, 1H), 2.51-2.48 (m, 2H). ESI MS m/z=402.7 (M+1)
Example 283
N1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)butane-
-1,4-diamine 283
[0431] Following the procedures Example 271,
3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)me-
thyl)-1H-pyrazolo[3,4-c]pyridine and butane-1,4-diamine were
reacted and the product was deprotected to give 283 as a yellow
solid (20 mg, 28%) over two steps. .sup.1H NMR (400 MHz, DMSO)
.delta. 9.19-9.21 (m, 1H), 9.12-9.13 (m, 2H), 8.53-8.60 (m, 2H),
7.60-7.63 (m, 1H) 7.51-7.54 (m, 1H), 7.44-7.46 (m, 1H), 6.53 (d,
J=6.4 Hz, 1H), 3.65 (t, J=1.2 Hz, 2H), 2.93 (t, J=1.2 Hz, 2H),
1.80-1.85 (m, 4H). ESI MS m/z=360 (M+1)
Example 284
3-(4,5-dihydrofuran-3-yl)-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine
284
[0432] Following the procedures Example 281,
3-iodo-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine from Example 4
and
2-(4,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
were reacted to give 284 as a white solid (0.1 g, 40%). 1H NMR (400
MHz, DMSO): .delta. 9.42 (s, 1H), 9.09 (s, 1H), 8.56-8.57 (m, 2H),
8.51 (s, 1H), 7.86 (s, 1H), 7.47-7.49 (m, 1H), 4.46-4.50 (m, 2H),
3.12-3.14 (m, 2H). ESI MS m/z=265 (M+1)
Example 285
(R)-1-(6-(5-(1-ethyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyrid-
in-2-yl)piperidin-3-amine 285
[0433] Following the procedures as described in Example 189,
3-(6-fluoropyridin-2-yl)-5-(1-ethyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyr-
an-2-yl)-1H-pyrazolo[3,4-c]pyridine and (R)-tert-butyl
piperidin-3-ylcarbamate were reacted. The product was deprotected
and purified to give 285 as a white solid (41.6% over two steps).
.sup.1H NMR (400 MHz, DMSO) .delta. 9.02 (s, 1H), 8.60 (s, 1H),
8.34 (s, 1H), 7.97 (s, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.42 (d, J=7.4
Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 4.45 (d, J=8.7 Hz, 1H), 4.28-4.12
(m, 3H), 2.98 (t, J=10.9 Hz, 1H), 2.82-2.72 (m, 2H), 2.03-1.93 (m,
1H), 1.86-1.77 (m, 1H), 1.67-1.51 (m, 1H), 1.42 (t, J=7.3 Hz, 3H),
1.38-1.26 (m, 1H); 3 protons not seen. LC/MS: m/z 389.2 [M+1]
Example 286
1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin--
2-yl)-3-(trifluoromethyl)pyrrolidin-3-amine 286
[0434] Following the procedures as described in Example 189,
3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-py-
ran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl
3-(trifluoromethyl)pyrrolidin-3-ylcarbamate were reacted. The
product was deprotected and purified to give 286 as a white solid
(47.3% over two steps). .sup.1H NMR (400 MHz, DMSO) .delta. 9.02
(s, 1H), 8.65 (s, 1H), 8.09 (s, 1H), 7.86 (s, 1H), 7.65 (t, J=7.9
Hz, 1H), 7.44 (d, J=7.4 Hz, 1H), 6.51 (d, J=8.3 Hz, 1H), 3.91-3.86
(m, 4H), 3.84-3.65 (m, 3H), 2.47 (s, 2H), 2.38-2.27 (m, 1H), 2.05
(dd, J=12.3, 6.1 Hz, 1H); 1 proton not seen. LC/MS: m/z 429.2
[M+1]
Example 287
(R)-1-(3-bromo-6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin--
2-yl)pyrrolidin-3-amine 287
Step 1: 3-bromo-2-fluoro-6-iodopyridine
##STR00510##
[0436] To a solution of 2-fluoropyridin-3-amine (5.00 g, 44.60
mmol) in DMF (100 mL) was added N-iodosuccinimide (11.04 g, 49.06
mmol). The resulting mixture was stirred overnight. The reaction
mixture was partitioned between EtOAc and water. The organic layer
was dried with MgSO4 and concentrated. The residue was purified on
silica eluted 0 to 50% EtOAc in Heptane.
2-fluoro-6-iodopyridin-3-amine was obtained as a dark tan solid
(8.8674 g, 83%). To an ice cooled mixture of tert-Butyl nitrite
(356.8 uL, 3.000 mmol) and Copper(II) bromide (536.0 mg, 2.400
mmol) in Acetonitrile (5 mL) was added
2-fluoro-6-iodopyridin-3-amine was obtained as a dark tan solid
(476.0 mg, 2.000 mmol). The resulting mixture was stirred overnight
allowing warming to room temperature. The mixture was filtered
through Celite. The filtrated was concentrated. The residue was
partitioned between Et2O and saturated NH4Cl. The organic layer was
dried with MgSO4, and then concentrated. The residue was purified
on silica eluted with 0 to 20% EtOAc in Heptane.
3-Bromo-2-fluoro-6-iodopyridine was obtained as a yellow solid
(407.1 mg, 57%)
Step 2:
3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethyl-
silyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine
##STR00511##
[0438] To an argon protected mixture of
5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(trimethylstannyl-
)-1H-pyrazolo[3,4-c]pyridine (239 mg, 0.489 mmol) and
3-bromo-2-fluoro-6-iodopyridine (162.3 mg, 0.538 mmol) in
N,N-Dimethylformamide (5 mL, 60 mmol) was added Cesium fluoride
(148 mg, 0.98 mmol). Tetrakis(triphenylphosphine)palladium(0)
(56.482 mg, 0.048878 mmol) and Copper(I) iodide (18.618 mg,
0.097757 mmol) were then added and the resulting mixture was
stirred at 40.degree. C. for 2 hours. The mixture was cooled to
room temperature, filtered through Celite.RTM.. The filter cake was
washed with EtOAc. The organic layer was washed with brine, dried
with MgSO4, and then concentrated. The residue was purified on
silica eluted with 0 to 100% EtOAc in Heptane to afford
3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)e-
thoxy)methyl)-1H-pyrazolo[3,4-c]pyridine as a light yellow oil,
which solidified upon standing (208.1 mg, 85%).
Step 3
[0439] Following the procedures as described in Example 241 and
starting with
3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsi-
lyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and (R)-tert-butyl
pyrrolidin-3-ylcarbamate, 287 was obtained as an off-white solid
(12.2 mg, 34%) over two steps. 1H NMR (400 MHz, DMSO) .delta. 9.27
(s, 1H), 9.22 (s, 1H), 9.02 (s, 1H), 8.60 (d, J=4.6 Hz, 1H), 8.41
(d, J=8.0 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.62 (dd, J=11.8, 7.2
Hz, 3H), 7.58-7.49 (m, 3H), 7.45 (d, J=8.0 Hz, 1H), 4.01-3.92 (m,
2H), 3.64-3.51 (m, 3H), 2.10 (dt, J=12.0, 5.9 Hz, 1H), 1.82-1.72
(m, 1H);
[0440] ESI MS m/z=358.2 (M+1)
Example 288
1-(3-methyl-6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-y-
l)piperidin-4-ol 288
[0441] Following the procedures as described in Examples 241, 243,
and 287 and starting with
3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)e-
thoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and piperidin-4-ol, 288
was obtained as an off-white solid (20.4 mg, 29%) over three steps.
1H NMR (400 MHz, DMSO) .delta. 13.85 (s, 1H), 9.25 (d, J=1.5 Hz,
1H), 9.20 (s, 1H), 9.09 (s, 1H), 8.61 (d, J=3.7 Hz, 1H), 8.41 (d,
J=8.0 Hz, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.63 (d, J=7.7 Hz, 1H), 7.55
(dd, J=7.9, 4.8 Hz, 1H), 4.73 (d, J=4.0 Hz, 1H), 3.74 (dd, J=8.7,
4.3 Hz, 1H), 3.61 (d, J=12.7 Hz, 2H), 3.06 (t, J=10.3 Hz, 2H), 2.31
(s, 3H), 1.95 (d, J=10.4 Hz, 2H), 1.65 (q, J=9.2 Hz, 2H); ESI MS
m/z=387.2 (M+1)
Example 289
(S)-1-(3-bromo-6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin--
2-yl)piperidin-3-amine 289
[0442] Following the procedures as described in Example 241 and
starting with
3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsi-
lyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and (S)-tert-butyl
piperidin-3-ylcarbamate, 289 was obtained as an off-white solid
(17.8 mg, 22.32%) over two steps. 1H NMR (400 MHz, DMSO) .delta.
9.31 (d, J=1.8 Hz, 1H), 9.23 (s, 1H), 9.03 (s, 1H), 8.60 (d, J=4.7
Hz, 1H), 8.46 (d, J=7.9 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.71 (d,
J=8.1 Hz, 1H), 7.62 (dd, J=11.8, 7.1 Hz, 1H), 7.52 (dd, J=8.0, 4.8
Hz, 1H), 3.92 (d, J=10.0 Hz, 1H), 3.84 (d, J=11.7 Hz, 1H), 2.89
(dt, J=16.9, 10.7 Hz, 2H), 2.82-2.75 (m, 1H), 1.96 (d, J=12.6 Hz,
1H), 1.90-1.71 (m, 2H), 1.27 (dd, J=20.9, 9.6 Hz, 1H); ESI MS
m/z=450.1 (M+1)
Example 290
(R)-1-(3-bromo-6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin--
2-yl)piperidin-3-amine 290
[0443] Following the procedures as described in Example 241 and
starting with
3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsi-
lyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and (R)-tert-butyl
piperidin-3-ylcarbamate, 290 was obtained as an off-white solid
(19.7 mg, 35.9%) over two steps. 1H NMR (400 MHz, DMSO) .delta.
9.31 (s, 1H), 9.22 (s, 1H), 9.03 (s, 1H), 8.59 (d, J=4.7 Hz, 1H),
8.46 (d, J=8.0 Hz, 1H), 8.05 (d, J=8.1 Hz, 1H), 7.70 (d, J=8.1 Hz,
1H), 7.62 (dd, J=11.8, 7.1 Hz, 1H), 7.54 (ddd, J=12.7, 7.2, 4.0 Hz,
2H), 3.92 (d, J=9.3 Hz, 1H), 3.84 (d, J=12.1 Hz, 1H), 2.88 (d,
J=12.9 Hz, 2H), 2.81-2.69 (m, 1H), 1.95 (d, J=12.6 Hz, 1H),
1.90-1.69 (m, 2H), 1.26 (dd, J=22.3, 7.8 Hz, 1H); ESI MS m/z=450.1
(M+1)
Example 291
(R)-1-(3-bromo-6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin--
2-yl)piperidin-3-ol 291
[0444] Following the procedures as described in Example 241 and
starting with
3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsi-
lyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and
(R)-piperidin-3-ol hydrochloride, 291 was obtained as an off-white
solid (11.0 mg, 29.9%) over two steps. 1H NMR (400 MHz, DMSO)
.delta. 9.31 (d, J=1.8 Hz, 1H), 9.24 (s, 1H), 9.01 (s, 1H), 8.60
(d, J=4.0 Hz, 1H), 8.44 (d, J=8.1 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H),
7.70 (d, J=8.1 Hz, 1H), 7.51 (dd, J=8.0, 4.8 Hz, 1H), 4.93 (d,
J=4.4 Hz, 1H), 3.97 (d, J=11.6 Hz, 1H), 3.83 (d, J=12.2 Hz, 1H),
3.74 (dd, J=9.2, 4.8 Hz, 1H), 2.99-2.81 (m, 2H), 2.02 (d, J=9.1 Hz,
1H), 1.88 (d, J=13.3 Hz, 1H), 1.72 (dd, J=22.7, 10.5 Hz, 1H), 1.39
(dd, J=22.0, 8.0 Hz, 1H); ESI MS m/z=451.1 (M+1)
Example 292
1-(3-bromo-6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl-
)piperidin-4-ol 292
[0445] Following the procedures as described in Example 241 and
starting with
3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsi-
lyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and piperidin-4-ol,
292 was obtained as an off-white solid (9.50 mg, 26.8%) over two
steps. 1H NMR (400 MHz, DMSO) .delta. 9.26-9.20 (m, 2H), 8.99 (s,
1H), 8.61 (d, J=3.7 Hz, 1H), 8.41 (d, J=7.9 Hz, 1H), 8.06 (d, J=8.1
Hz, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.55 (dd, J=8.0, 4.8 Hz, 1H), 4.75
(d, J=3.7 Hz, 1H), 3.91-3.71 (m, 3H), 3.18 (d, J=10.1 Hz, 2H), 1.96
(d, J=11.1 Hz, 2H), 1.65 (dd, J=18.8, 9.2 Hz, 2H); ESI MS m/z=451.2
(M+1)
Example 293
(R)-1-(3-bromo-6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin--
2-yl)pyrrolidin-3-ol 293
[0446] Following the procedures as described in Example 241 and
starting with
3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsi-
lyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and
(R)-pyrrolidin-3-ol hydrochloride, 293 was obtained as an off-white
solid (3.50 mg, 9.60%) over two steps. ESI MS m/z=437.1 (M+1)
Example 294
1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin--
2-yl)piperidin-4-ol 294
[0447] Following the procedures as described in Example 189,
3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-py-
ran-2-yl)-1H-pyrazolo[3,4-c]pyridine and piperidin-4-ol were
reacted. The product was deprotected and purified to give 294 as a
white solid (56.1% over two steps). .sup.1H NMR (400 MHz, DMSO)
.delta. 13.69 (broad s, 1H), 9.03 (s, 1H), 8.53 (s, 1H), 8.11 (s,
1H), 7.82 (s, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.42 (d, J=7.4 Hz, 1H),
6.87 (d, J=8.5 Hz, 1H), 4.73 (d, J=3.2 Hz, 1H), 4.24-4.15 (m, 2H),
3.91 (s, 3H), 3.6-3.76 (m, 1H), 3.37-3.29 (m, 2H), 1.97-1.86 (m,
2H), 1.58-1.44 (m, 2H). LC/MS: m/z 376.2 [M+1]
Example 295
2-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-2,8-diazaspiro[4.5]dec-
an-1-one 295
Step 1: benzyl
1-oxo-2-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-
o[3,4-c]pyridin-3-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate
##STR00512##
[0449] A solution containing
3-iodo-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[-
3,4-c]pyridine (0.196 g, 0.434 mmol), benzyl
1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (0.250 g, 0.867
mmol), N,N'-Dimethylethylenediamine (0.103 mL, 0.954 mmol),
Copper(I) iodide (0.0908 g, 0.477 mmol) and Cesium Carbonate (0.311
g, 0.954 mmol) in 1,4-Dioxane (7.08 mL, 90.7 mmol) was stirred at
75.degree. C. for 2 h. The reaction was filtered thru celite and
concentrated. The crude product purified by Isco column (EtOAc/Hep
eluted at 50% EtOAc) to give benzyl
1-oxo-2-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-
o[3,4-c]pyridin-3-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (140
mg, 52.7% yield). ESI MS m/z=613.1 (M+1).
Step 2
[0450] A solution of benzyl
1-oxo-2-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-
o[3,4-c]pyridin-3-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate
(0.140 g, 0.229 mmol) in 2.00 M of Hydrogen chloride in Water (16.2
mL) was stirred at 100.degree. C. for 18 h. The reaction was
concentrated then submitted for rHPLC to give 295 (21.2 mg, 26.5%
yield). ESI MS m/z=349.2 (M+1). .sup.1H NMR (400 MHz, DMSO) .delta.
9.19 (d, J=1.8 Hz, 1H), 9.07 (s, 1H), 8.67 (s, 1H), 8.57 (d, J=4.6
Hz, 1H), 8.33 (d, J=8.0 Hz, 1H), 7.51 (dd, J=7.9, 4.7 Hz, 1H), 3.97
(t, J=7.0 Hz, 2H), 2.92 (d, J=12.6 Hz, 2H), 2.63 (dd, J=21.4, 9.3
Hz, 2H), 2.20 (t, J=7.0 Hz, 2H), 1.74 (td, J=12.5, 4.1 Hz, 2H),
1.48 (d, J=13.0 Hz, 2H)
Example 296
1-(piperidin-4-ylmethyl)-3-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-y-
l)imidazolidin-2-one 296
Step 1:
1-acetyl-3-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c-
]pyridin-3-yl)imidazolidin-2-one
##STR00513##
[0452] A solution containing
5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine
(1.00 g, 2.45 mmol), 1-acetylimidazolidin-2-one (0.3768 g, 2.941
mmol), N,N'-Dimethylethylenediamine (0.528 mL, 4.90 mmol),
Copper(I) iodide (0.467 g, 2.45 mmol) and Potassium carbonate
(0.4064 g, 2.941 mmol) in 1,4-Dioxane (40.0 mL, 512 mmol) was
stirred at 75.degree. C. for 2 h. The reaction was filtered thru
celite and concentrated. The crude product purified by Isco column
(1% MeOH/EtOAc/Hep eluted at 55% EtOAc) to give
1-acetyl-3-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridi-
n-3-yl)imidazolidin-2-one (620 mg, 62% yield). ESI MS m/z=408.1
(M+1).
Step 2:
1-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c-
]pyridin-3-yl)imidazolidin-2-one
##STR00514##
[0454] To a solution containing
1-acetyl-3-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridi-
n-3-yl)imidazolidin-2-one (0.295 g, 0.722 mmol), 3-pyridineboronic
acid pinacol ester (0.444 g, 2.17 mmol),
1,1'-Bis(diphenylphosphino)ferrocenepalladium (II) chloride (0.0472
g, 0.0578 mmol) in Acetonitrile (5.47 mL, 105 mmol) was added 1.00
M of Potassium acetate in Water (1.44 mL) and 1.00 M of Sodium
carbonate in Water (1.44 mL). The reaction was stirred at
100.degree. C. for 3 h. The reaction is filtered thru celite. The
crude product was diluted in EtOAc then washed with water and sat.
NaCl. The organic layer was dried Na2SO4, filtered, and
concentrated to give
1-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridi-
n-3-yl)imidazolidin-2-one. ESI MS m/z=365.2 (M+1).
Step 3
[0455] To a solution of
1-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridi-
n-3-yl)imidazolidin-2-one (0.120 g, 0.329 mmol) dissolved in
N,N-Dimethylformamide (3.43 mL) and cooled to 0.degree. C. was
added NaH in Oil (6:4, Sodium hydride:Mineral Oil, 26.3 mg). The
reaction mixture was stirred at RT for 30 mins then cooled to
0.degree. C. 4-bromomethyl-piperidine-1-carboxylic acid tert-butyl
ester (0.183 g, 0.659 mmol) was added. The reaction was stirred at
RT for 18 hr. The mixture was quenched with H2O then extracted with
EtOAc. The organic layers was dried, filtered, and concentrated to
give tert-butyl
4-((2-oxo-3-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,-
4-c]pyridin-3-yl)imidazolidin-1-yl)methyl)piperidine-1-carboxylate
which was dissolved in 4.0 M of Hydrogen chloride in 1,4-Dioxane
(6.00 mL) and 1,4-Dioxane (3.00 mL, 38.4 mmol) was stirred at RT 18
h. The reaction was concentrated and submitted for rHPLC
purification to give 296 (11.6 mg, 9.3% yield). ESI MS m/z=378.2
(M+1). .sup.1H NMR (400 MHz, DMSO) .delta. 9.17 (s, 1H), 9.03 (s,
1H), 8.78 (s, 1H), 8.55 (d, J=4.7 Hz, 1H), 8.30 (d, J=8.0 Hz, 1H),
7.50 (dd, J=8.0, 4.7 Hz, 1H), 4.03-3.93 (m, 2H), 3.65-3.56 (m, 2H),
3.11 (d, J=7.2 Hz, 2H), 2.92 (d, J=12.0 Hz, 2H), 2.42 (d, J=10.9
Hz, 1H), 1.79-1.67 (m, 1H), 1.59 (d, J=11.8 Hz, 2H), 1.05 (dd,
J=21.5, 9.9 Hz, 2H)
Example 297
2-methyl-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl-
)pyridin-2-ylamino)propan-2-ol 297
[0456] Following the procedures as described in Example 189,
3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-py-
ran-2-yl)-1H-pyrazolo[3,4-c]pyridine and
1-amino-2-methyl-propan-2-ol were reacted. The product was
deprotected and purified to give 297 as a white solid (87% over two
steps). .sup.1H NMR (400 MHz, DMSO) .delta. 13.62 (broad s, 1H),
9.01 (s, 1H), 8.72 (s, 1H), 8.25 (s, 1H), 7.98 (s, 1H), 7.47 (t,
J=7.8 Hz, 1H), 7.31 (d, J=7.3 Hz, 1H), 6.63-6.56 (m, 2H), 4.73 (s,
1H), 3.89 (s, 3H), 3.56 (d, J=5.8 Hz, 2H), 1.25 (s, 6H). LC/MS: m/z
364.2 [M+1]
Example 298
(S)-1-(3-(6-(3-aminopiperidin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-c]pyridin-
-5-yl)urea 298
[0457] Following the Buchwald-Hartwig procedure of Example 224,
tert-butyl
(3S)-1-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-
-3-yl)pyridin-2-yl)piperidin-3-ylcarbamate and
(1,1-dimethylethyl)urea were reacted and deprotected by the
procedure of Example 229. The mixture was purified via reverse
phase HPLC using a gradient of MeOH in water with 0.1% NH.sub.4OH
to afford 20 mg (23%) of 298 over three steps. ESI MS m/z 353.2
(M+1). 1H NMR (400 MHz, DMSO): 9.14 (s, 1H), 8.96 (s, 1H), 8.75 (s,
1H), 8.40 (s, 2H), 7.63 (t, J=8.0 Hz, 1H), 7.45 (d, J=7.4 Hz, 1H),
6.80 (d, J=8.5 Hz, 1H), 6.48 (s, 2H), 4.92 (d, J=11.4 Hz, 1H), 4.05
(d, J=12.9 Hz, 1H), 3.09 (m, 1H), 2.94-2.77 (m, 2H), 2.54 (s, 2H),
2.05 (d, J=9.7 Hz, 1H), 1.84 (d, J=13.1, Hz, 1H), 1.64-1.42 (m,
2H)
Example 299
(1S,3R)-3-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl-
oxy)cyclohexanamine 299
Step 1: tert-Butyl (1S,3S)-3-hydroxycyclohexylcarbamate
##STR00515##
[0459] A solution of 0.5238 g (2.4 mmol) of
di-tert-butyldicarbonate in 5 ml of THF and 0.6 ml of 4.0 M of
sodium hydroxide in water were added dropwise to a solution of
230.3 mg (2.0 mmol) of (1S,3S)-3-aminocyclohexanol in 6 ml of
tetrahydrofuran and 4 ml of water at 0.degree. C. The mixture was
stirred for 18 hours, diluted with water and extracted with ethyl
acetate. The organic extracts were washed with water, brine, dried
over MgSO4 and concentrated to afford 434 mg (100%) of tert-Butyl
(1S,3S)-3-hydroxycyclohexylcarbamate as a crystalline residue.
Step 2: tert-Butyl
(1S,3R)-3-(6-bromopyridin-2-yloxy)cyclohexylcarbamate
##STR00516##
[0461] A solution of 0.473 mL (2.4 mmol) of
diisopropylazodicarboxylate in 2 ml of tetrahydrofuran was added
dropwise to a mixture of 454 mg (2.0 mmol) of tert-butyl
(1S,3S)-3-hydroxycyclohexylcarbamate, 418 mg (2.40 mmol) of
2-bromo-6-hydroxypyridine and 629.5 mg (2.4 mmol) of
triphenylphosphine in 5 ml of tetrahydrofuran at 0-5.degree. C. The
mixture was stirred for 18 hours. The mixture was concentrated, the
residue purified via silica gel chromatography using a gradient of
ethyl acetate in heptane to afford 222 mg (30%) of tert-Butyl
(1S,3R)-3-(6-bromopyridin-2-yloxy)cyclohexylcarbamate. ESI MS m/z
370.9 (M+1).
Step 3: tert-Butyl
(1S,3R)-3-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-py-
razolo[3,4-c]pyridin-3-yl)pyridin-2-yloxy)cyclohexylcarbamate
##STR00517##
[0463] A mixture of 147 mg (0.3 mmol) of
5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(trimethylstannyl-
)-1H-pyrazolo[3,4-c]pyridine, 123 mg, 0.33 mmol) of tert-butyl
(1S,3R)-3-(6-bromopyridin-2-yloxy)cyclohexylcarbamate, 109 mg (0.72
mmol) of Cesium fluoride, 35 mg (0.03 mmol) of
tetrakis(triphenylphosphine)palladium(0) and 11.4 mg (0.06 mmol) of
copper(I) iodide in 2 ml of N,N-dimethylformamide was heated at
50.degree. C. for 2 hours in a Stille coupling. The mixture was
diluted with water and extracted with ethyl acetate. The organic
extracts were washed with water, brine, dried over MgSO4 and
concentrated. The residue was purified via silica gel
chromatography using a gradient of ethyl acetate in heptane to
afford 98 mg (53%) of tert-Butyl
(1S,3R)-3-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-py-
razolo[3,4-c]pyridin-3-yl)pyridin-2-yloxy)cyclohexylcarbamate. ESI
MS m/z 617.5 (M+1).
Step 4
[0464] tert-Butyl
(1S,3R)-3-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-py-
razolo[3,4-c]pyridin-3-yl)pyridin-2-yloxy)cyclohexylcarbamate was
deprotected by the procedure of Example 225 and purified via
reverse phase HPLC using a gradient of MeOH in water with 0.1%
NH.sub.4OH to afford 32 mg (61%) of 299. ESI MS m/z 387.2 (M+1). 1H
NMR (400 MHz, DMSO): 9.26 (d, J=1.7 Hz, 1H), 9.23 (s, 1H), 8.86 (s,
1H), 8.61 (d, J=4.7 Hz, 1H), 8.42 (d, J=8.0 Hz, 1H), 7.86-7.78 (m,
2H), 7.52 (dd, J=7.9, 4.8 Hz, 1H), 6.81-6.73 (m, 1H), 5.35 (m, 1H),
2.79-2.69 (m, 1H), 2.33 (m, 1H), 2.22 (s, 1H), 1.71 (m, 2H),
1.36-1.19 (m, 3H), 1.06-0.93 (m, 1H)
Example 300
(R)-1-(4-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyrimidin-2-yl)p-
iperidin-3-amine 300
Step 1:
3-(2-Chloropyrimidin-4-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)-
ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine
##STR00518##
[0466] Following the Stille coupling procedure of Example 299,
5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(trimethylstannyl-
)-1H-pyrazolo[3,4-c]pyridine and 2,4-dichloropyrimidine were
reacted. The product was purified via silica gel chromatography
using a gradient of ethyl acetate in heptane to afford 60 mg (50%)
of
3-(2-Chloropyrimidin-4-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)-
methyl)-1H-pyrazolo[3,4-c]pyridine. ESI MS m/z 439.2 (M+1).
Step 2
[0467] Following the procedure of Example 144,
3-(2-chloropyrimidin-4-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)-
methyl)-1H-pyrazolo[3,4-c]pyridine and (R)-tert-butyl
piperidin-3-ylcarbamate were reacted. The product was deprotected
by the procedure of Example 225 and purified via reverse phase HPLC
using a gradient of MeOH in water with 0.1% NH.sub.4OH to afford 32
mg (63%) of 300. ESI MS m/z 373.2 (M+1). 1H NMR (400 MHz, DMSO):
9.30 (s, 1H), 9.25 (s, 1H), 8.91 (s, 1H), 8.59 (dd, J=4.7, 1.2 Hz,
1H), 8.45 (t, J=8.1 Hz, 2H), 7.53 (dd, J=7.9, 4.7 Hz, 1H), 7.32 (d,
J=5.0 Hz, 1H), 4.71 (d, J=10.8 Hz, 1H), 4.61 (d, J=12.5 Hz, 1H),
3.15-3.06 (m, 1H), 2.91-2.83 (m, 1H), 2.82-2.73 (m, 1H), 1.96 (d,
J=11. Hz, 1H), 1.81 (d, J=13.4 Hz, 1H), 1.55 (d, J=12.1 Hz, 1H),
1.36 (td, J=12.2, 3.8 Hz, 1H)
Example 301
1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperaz-
in-2-one 301
Step 1:
3-(6-Bromopyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)eth-
oxy)methyl)-1H-pyrazolo[3,4-c]pyridine
##STR00519##
[0469] Following the Stille coupling procedure of Example 299,
5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(trimethylstannyl-
)-1H-pyrazolo[3,4-c]pyridine and 2,6-dibromopyridine were reacted.
The mixture was purified via silica gel chromatography using a
gradient of ethyl acetate in heptane to afford 81 mg (67%) of
3-(6-Bromopyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)met-
hyl)-1H-pyrazolo[3,4-c]pyridine. ESI MS m/z 482.2 (M+1).
Step 2
[0470] Following the procedure of Example 224,
3-(6-bromopyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)met-
hyl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl
3-oxopiperazine-1-carboxylate were reacted. The product was
deprotected by the procedure of Example 225 and purified via
reverse phase HPLC using a gradient of MeOH in water with 0.1%
NH.sub.4OH to afford 8.0 mg (20%) of 301 over two steps. ESI MS m/z
372.1 (M+1). 1H NMR (400 MHz, DMSO); 14.08 (s, 1H), 9.29 (d, J=2.0
Hz, 1H), 9.25 (s, 1H), 8.94 (s, 1H), 8.61 (dd, J=4.7, 1.3 Hz, 1H),
8.47-8.40 (m, 1H), 8.07-7.92 (m, 3H), 7.56 (dd, J=7.9, 4.8 Hz, 1H),
6.48 (s, 1H), 4.22 (t, J=5.4 Hz, 2H), 3.56 (s, 2H), 3.18 (t, J=5.4
Hz, 2H). m/z 372.1 (M+1)
Example 302
2-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)isonicotinamide
302
[0471] Following the Stille coupling procedure of Example 299,
5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(trimethylstannyl-
)-1H-pyrazolo[3,4-c]pyridine and 2-bromoisonicotinamide were
reacted. The product was deprotected by the procedure of Example
225 and purified via silica gel chromatography using a gradient of
methanol in dichloromethane to afford 10 mg (21%) of 302 over two
steps. ESI MS m/z 317.1 (M+1). 1H NMR (400 MHz, DMSO): 14.16 (s,
1H), 9.28 (d, J=12.0 Hz, 2H), 8.96 (s, 1H), 8.94 (d, J=5.1 Hz, 1H),
8.62 (d, J=5.3 Hz, 2H), 8.45 (d, J=8.0 Hz, 1H), 8.40 (s, 1H), 7.80
(d, J=5.1 Hz, 1H), 7.76 (s, 1H), 7.55 (dd, J=8.0, 4.7 Hz, 1H)
Example 303
1-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-(pyrrolidin-3-ylmeth-
yl)imidazolidin-2-one 303
[0472] Following the procedures in Example 296,
1-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridi-
n-3-yl)imidazolidin-2-one was converted to 303. ESI MS m/z=364.2
(M+1). .sup.1H NMR (400 MHz, DMSO) .delta. 9.17 (d, J=2.1 Hz, 1H),
9.05 (s, 1H), 8.81 (s, 1H), 8.57 (dd, J=4.7, 1.3 Hz, 1H), 8.31 (d,
J=8.0 Hz, 1H), 7.51 (dd, J=8.0, 4.7 Hz, 1H), 4.06-3.96 (m, 2H),
3.69-3.60 (m, 2H), 3.30 (dd, J=7.4, 3.5 Hz, 2H), 3.22-3.07 (m, 2H),
3.00 (dd, J=17.3, 9.1 Hz, 1H), 2.77 (dd, J=11.0, 7.1 Hz, 1H), 1.98
(dt, J=12.7, 7.6 Hz, 1H), 1.57 (dt, J=20.3, 7.6 Hz, 1H)
Example 305
(S)-1-(3-methyl-6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-
-2-yl)pyrrolidin-3-ol 305
[0473] Following the procedures as described in Example 241 and
starting with
3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsi-
lyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and
(S)-pyrrolidin-3-ol, 305 was obtained as an off-white solid (17 mg,
20%) over three steps. 1H NMR (400 MHz, DMSO) .delta. 9.25 (s, 1H),
9.18 (s, 1H), 9.09 (s, 1H), 8.59 (d, J=4.6 Hz, 1H), 8.40 (d, J=8.0
Hz, 1H), 7.53 (dd, J=7.9, 4.7 Hz, 1H), 7.47 (q, J=7.6 Hz, 2H), 4.96
(s, 1H), 4.43 (s, 1H), 4.00-3.87 (m, 2H), 3.75 (td, J=8.8, 3.9 Hz,
1H), 3.51 (d, J=11.0 Hz, 1H), 2.37 (s, 3H), 2.12-2.04 (m, 1H),
1.97-1.88 (m, 1H); ESI MS m/z=373.2 (M+1)
Example 306
(R)-1-(3-methyl-6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-
-2-yl)pyrrolidin-3-ol 306
[0474] Following the procedures as described in Examples 241, 243,
287, and starting with
3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)e-
thoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and (R)-pyrrolidin-3-ol
hydrochloride, 306 was obtained as an off-white solid (25.5 mg,
35%) over three steps. 1H NMR (400 MHz, DMSO) .delta. 9.25 (s, 1H),
9.18 (s, 1H), 9.09 (s, 1H), 8.60 (d, J=4.6 Hz, 1H), 8.40 (d, J=7.9
Hz, 1H), 7.54 (dd, J=7.9, 4.8 Hz, 1H), 7.51-7.44 (m, 2H), 4.96 (s,
1H), 4.43 (s, 1H), 4.00-3.88 (m, 2H), 3.80-3.70 (m, 1H), 3.51 (d,
J=10.2 Hz, 1H), 2.38 (s, 3H), 2.10-2.03 (m, 1H), 1.93 (s, 1H); ESI
MS m/z=373.2 (M+1)
Example 307
(S)-1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-vinylpyridin--
2-yl)piperidin-3-amine 307
[0475] A microwave reaction vial was charged with (S)-tert-butyl
1-(3-bromo-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-py-
razolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-3-ylcarbamate
(128.3 mg, 0.189 mmol),
4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (320 uL, 1.9 mmol),
1,1'-Bis(diphenylphosphino)ferrocenepalladium (II) chloride (15.4
mg, 0.0189 mmol), 1.00 M of Potassium acetate in Water (0.28 mL,
0.28 mmol), 1.00 M of Sodium carbonate in Water (0.28 mL, 0.28
mmol), and Acetonitrile (10 mL). The reaction mixture was heated
under microwave at 150.degree. C. for 5 minutes. The mixture was
concentrated, and the residue was purified on silica eluted with 0
to 100% EtOAc in Heptane to afford (S)-tert-butyl
1-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3-
,4-c]pyridin-3-yl)-3-vinylpyridin-2-yl)piperidin-3-ylcarbamate (107
mg, 91%).
[0476] The above (S)-tert-butyl
1-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3-
,4-c]pyridin-3-yl)-3-vinylpyridin-2-yl)piperidin-3-ylcarbamate
(23.7 mg, 0.038 mmol) was dissolved in Trifluoroacetic Acid (2 mL)
and Methylene chloride (2 mL). To the solution was add
Trifluoromethanesulfonic acid (50 uL, 0.6 mmol) and Triethylsilane
(30 uL, 0.19 mmol). The resulting mixture was stirred overnight at
room temperature. The mixture was then concentrated, and the
residue was purified by reverse phase HPLC to afford 307 as an
off-white solid (5.1 mg, 34%). 1H NMR (400 MHz, DMSO) .delta. 9.32
(d, J=1.9 Hz, 1H), 9.20 (s, 1H), 9.11 (s, 1H), 8.59 (d, J=3.8 Hz,
1H), 8.46 (d, J=8.0 Hz, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.82 (d, J=7.9
Hz, 1H), 7.52 (dd, J=8.0, 4.7 Hz, 1H), 6.80 (dd, J=17.7, 11.0 Hz,
1H), 5.88 (d, J=17.6 Hz, 1H), 5.38 (d, J=11.3 Hz, 1H), 3.77 (d,
J=9.7 Hz, 1H), 3.58 (d, J=12.1 Hz, 1H), 2.92-2.82 (m, 2H),
2.82-2.72 (m, 1H), 1.95 (d, J=12.7 Hz, 1H), 1.87-1.71 (m, 2H), 1.25
(dd, J=19.0, 10.7 Hz, 1H); ESI MS m/z=398.2 (M+1)
Example 308
(S)-1-(3-(prop-1-en-2-yl)-6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3--
yl)pyridin-2-yl)piperidin-3-amine 308
[0477] Following the procedures as described in Example 307 and
staring with
4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane, 308 was
obtained as an off-white solid (6.7 mg, 43%) over two steps. 1H NMR
(400 MHz, DMSO) .delta. 9.33 (d, J=1.8 Hz, 1H), 9.21 (s, 1H), 9.11
(s, 1H), 8.59 (d, J=3.6 Hz, 1H), 8.48 (d, J=8.0 Hz, 1H), 7.73 (d,
J=7.7 Hz, 1H), 7.58 (d, J=7.7 Hz, 1H), 7.51 (dd, J=8.0, 4.7 Hz,
1H), 5.23 (d, J=27.4 Hz, 2H), 4.00 (d, J=10.2 Hz, 1H), 3.83 (d,
J=12.2 Hz, 1H), 2.76 (ddd, J=30.9, 18.3, 10.1 Hz, 3H), 2.13 (s,
3H), 1.93 (d, J=8.9 Hz, 1H), 1.82-1.62 (m, 2H), 1.22 (dd, J=22.4,
7.9 Hz, 1H); ESI MS m/z=412.2 (M+1)
Example 309
(R)-1-(3-methyl-6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-
-2-yl)piperidin-3-ol 309
[0478] Following the procedures as described in Examples 241, 243,
287, and starting with
3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)e-
thoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and (R)-piperidin-3-ol
hydrochloride, 309 was obtained as an off-white solid (18 mg, 34%)
over three steps. 1H NMR (400 MHz, DMSO) .delta. 13.87 (s, 1H),
9.31 (d, J=1.7 Hz, 1H), 9.21 (s, 1H), 9.11 (s, 1H), 8.60 (d, J=3.6
Hz, 1H), 8.45 (d, J=8.0 Hz, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.63 (d,
J=7.7 Hz, 1H), 7.51 (dd, J=8.0, 4.7 Hz, 1H), 4.88 (d, J=4.4 Hz,
1H), 3.80-3.65 (m, 2H), 3.53 (d, J=12.2 Hz, 1H), 2.84 (dt, J=20.1,
9.9 Hz, 2H), 2.31 (s, 3H), 2.00 (d, J=11.7 Hz, 1H), 1.86 (d, J=13.5
Hz, 1H), 1.77-1.63 (m, 1H), 1.39 (dd, J=21.1, 8.2 Hz, 1H); ESI MS
m/z=387.2 (M+1)
Example 310
(R)-1-(3-methyl-6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-
-2-yl)piperidin-3-amine 310
[0479] Following the procedures as described in Examples 241, 243,
287, and starting with
3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)e-
thoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and (R)-tert-butyl
piperidin-3-ylcarbamate, 310 was obtained as an off-white solid (46
mg, 42%) over three steps. 1H NMR (400 MHz, DMSO) .delta. 9.30 (s,
1H), 9.22 (s, 1H), 9.08 (s, 1H), 8.61 (d, J=4.6 Hz, 1H), 8.45 (d,
J=7.9 Hz, 1H), 8.32 (s, 2H), 7.77 (d, J=7.7 Hz, 1H), 7.66 (d, J=7.7
Hz, 1H), 7.54 (dd, J=7.9, 4.7 Hz, 1H), 3.70 (s, 2H), 2.90 (s, 2H),
1.98 (s, 1H), 1.88 (s, 1H), 1.77 (s, 1H), 1.43 (s, 1H); ESI MS
m/z=386.3 (M+1)
Example 311
(R)-1-(3-methyl-6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-
-2-yl)azepan-4-amine 311
[0480] Following the procedures as described in Examples 241, 243,
287,
3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)e-
thoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and (R)-benzyl
azepan-4-ylcarbamate hydrochloride were reacted to give (R)-benzyl
1-(3-methyl-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-p-
yrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-ylcarbamate, which
was dissolved in Trifluoroacetic Acid (5 mL) and Methylene chloride
(5 mL), and treated with Trifluoromethanesulfonic acid (5 eq.) and
Triethylsilane (5 eq.). The resulting mixture was stirred at room
temperature for 2 days. The mixture was then concentrated, and the
residue was purified by reverse phase HPLC to afford 311 as an
off-white solid (31 mg, 28%) over three steps. 1H NMR (400 MHz,
DMSO) .delta. 9.23 (d, J=14.6 Hz, 2H), 8.99 (s, 1H), 8.61 (d, J=4.6
Hz, 1H), 8.42 (d, J=8.0 Hz, 1H), 8.29 (s, 1H), 7.59 (ddd, J=14.0,
12.7, 6.2 Hz, 3H), 3.82 (dd, J=10.5, 5.8 Hz, 1H), 3.72 (t, J=9.3
Hz, 1H), 3.66-3.61 (m, 1H), 3.55-3.50 (m, 2H), 2.34 (s, 3H), 2.17
(d, J=9.2 Hz, 1H), 2.06-1.80 (m, 4H), 1.72 (q, J=10.4 Hz, 1H); ESI
MS m/z=400.2 (M+1)
Example 312
(S)-1-(3-bromo-6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin--
2-yl)azepan-4-amine 312
[0481] Following the procedures of Examples 241 and 287,
3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)e-
thoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and (5)-benzyl
azepan-4-ylcarbamate were reacted to give (S)-benzyl
1-(3-bromo-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-py-
razolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-ylcarbamate, which
was dissolved in Trifluoroacetic Acid (5 mL) and Methylene chloride
(5 mL), and treated with Trifluoromethanesulfonic acid (5 eq.) and
Triethylsilane (5 eq.). The resulting mixture was stirred at room
temperature for 2 days. The mixture was then concentrated, and the
residue was purified by reverse phase HPLC to afford 312 as an
off-white solid (21 mg, 37%) over two steps. 1H NMR (400 MHz, DMSO)
.delta. 9.25 (s, 2H), 8.91 (s, 1H), 8.62 (d, J=3.7 Hz, 1H), 8.42
(d, J=8.0 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H),
7.56 (dd, J=7.8, 4.7 Hz, 1H), 4.02 (d, J=15.1 Hz, 1H), 3.91-3.83
(m, 1H), 3.78 (dd, J=11.6, 6.8 Hz, 1H), 3.69-3.58 (m, 1H), 2.19 (s,
1H), 1.99 (d, J=38.8 Hz, 4H), 1.71 (dd, J=21.2, 10.1 Hz, 1H); ESI
MS m/z=464.01 (M+1)
Example 313
(R)-1-(3-bromo-6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin--
2-yl)azepan-4-amine 313
[0482] Following the procedures of Examples 241 and 287,
3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)e-
thoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and (R)-benzyl
azepan-4-ylcarbamate hydrochloride were reacted to give (R)-benzyl
1-(3-bromo-645-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyr-
azolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-ylcarbamate, which
was dissolved in Trifluoroacetic Acid (5 mL) and Methylene chloride
(5 mL), and treated with Trifluoromethanesulfonic acid (5 eq.) and
Triethylsilane (5 eq.). The resulting mixture was stirred at room
temperature for 2 days. The mixture was then concentrated, and the
residue was purified by reverse phase HPLC to afford 313 as an
off-white solid (14.2 mg, 25.5%) over two steps. 1H NMR (400 MHz,
DMSO) .delta. 9.24 (s, 2H), 8.91 (s, 1H), 8.61 (d, J=3.6 Hz, 1H),
8.42 (d, J=8.0 Hz, 1H), 8.35 (s, 1H), 8.03 (d, J=8.0 Hz, 1H),
7.62-7.51 (m, 2H), 4.00 (d, J=14.6 Hz, 2H), 3.90-3.81 (m, 2H), 3.77
(dd, J=11.4, 6.7 Hz, 2H), 3.67-3.59 (m, 3H), 2.18 (s, 1H), 1.98
(dd, J=31.3, 18.3 Hz, 4H), 1.75-1.59 (m, 1H); ESI MS m/z=464.01
(M+1)
Example 314
(S)-1-(3-methyl-6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-
-2-yl)azepan-4-amine 314
[0483] Following the procedures of Example 241,
3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)e-
thoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and (S)-benzyl
azepan-4-ylcarbamate were reacted to give (S)-benzyl
1-(3-methyl-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-p-
yrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-ylcarbamate, which
was dissolved in Trifluoroacetic Acid (5 mL) and Methylene chloride
(5 mL), and treated with Trifluoromethanesulfonic acid (5 eq.) and
Triethylsilane (5 eq.). The resulting mixture was stirred at room
temperature for 2 days. The mixture was then concentrated, and the
residue was purified by reverse phase HPLC to afford 314 as an
off-white solid (34.1 mg, 30.5%) over three steps. 1H NMR (400 MHz,
DMSO) .delta. 9.25 (d, J=1.9 Hz, 1H), 9.21 (s, 1H), 8.99 (s, 1H),
8.61 (d, J=4.7 Hz, 1H), 8.41 (d, J=7.9 Hz, 1H), 8.34 (s, 1H), 7.63
(t, J=10.2 Hz, 1H), 7.59-7.53 (m, 1H), 2.34 (s, 3H), 2.15 (s, 1H),
1.95 (dd, J=29.7, 7.9 Hz, 4H), 1.77-1.64 (m, 1H); ESI MS m/z=400.12
(M+1)
Example 315
(S)-1-(3-methyl-6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-
-2-yl)piperidin-3-amine 315
[0484] Following the procedures of Examples 241, 243, 287, and
starting with
3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsi-
lyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and (S)-tert-butyl
piperidin-3-ylcarbamate, 315 was obtained as an off-white solid (37
mg, 29%) over three steps. 1H NMR (400 MHz, DMSO) .delta. 9.31 (d,
J=2.0 Hz, 1H), 9.20 (s, 1H), 9.13 (s, 1H), 8.59 (dd, J=4.7, 1.3 Hz,
1H), 8.46 (d, J=8.0 Hz, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.62 (d, J=7.7
Hz, 1H), 7.52 (dd, J=8.0, 4.7 Hz, 1H), 3.67 (d, J=9.6 Hz, 1H), 3.53
(d, J=11.9 Hz, 1H), 2.89 (dd, J=11.6, 7.5 Hz, 1H), 2.81 (t, J=10.3
Hz, 1H), 2.75-2.65 (m, 1H), 2.31 (s, 3H), 1.95 (d, J=12.4 Hz, 1H),
1.84 (d, J=13.4 Hz, 1H), 1.75 (t, J=11.7 Hz, 1H), 1.24 (dt, J=12.0,
6.0 Hz, 1H); ESI MS m/z=386.1 (M+1)
Example 316
(R)-1-(3-methyl-6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-
-2-yl)pyrrolidin-3-amine 316
[0485] A microwave reaction vial was charged with (R)-tert-butyl
1-(3-bromo-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-py-
razolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-ylcarbamate
(124.5 mg, 0.1867 mmol), Methyl boronic acid (111.76 mg, 1.867
mmol), 1,1'-Bis(diphenylphosphino)ferrocenepalladium (II) chloride
(15.2 mg, 0.01876 mmol), 1.00 M of Potassium acetate in Water (0.28
mL, 0.28 mmol), 1.00 M of Sodium carbonate in Water (0.28 mL, 0.28
mmol), and Acetonitrile (10 mL). The reaction mixture was heated
under microwave at 150.degree. C. for 5 minutes. The mixture was
concentrated, and the residue was purified on silica eluted with 0
to 100% EtOAc in Heptane to afford (R)-tert-butyl
1-(3-methyl-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-p-
yrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-ylcarbamate
(43.8 mg, 39%).
[0486] To (R)-tert-butyl
1-(3-methyl-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-p-
yrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-ylcarbamate in
MeOH (4 mL) was added 4.0 M of Hydrogen chloride in 1,4-Dioxane (6
mL). The resulting mixture was stirred overnight at room
temperature. The mixture was then concentrated, and the residue was
purified by reverse phase HPLC to afford 316 as an off-white solid
(15.4 mg, 56.9%). 1H NMR (400 MHz, DMSO) .delta. 9.27 (d, J=1.7 Hz,
1H), 9.19 (s, 1H), 9.12 (s, 1H), 8.59 (d, J=3.8 Hz, 1H), 8.41 (d,
J=8.0 Hz, 1H), 7.53 (dd, J=7.9, 4.8 Hz, 1H), 7.51-7.43 (m, 2H),
3.85 (dd, J=9.5, 5.6 Hz, 2H), 3.77 (dd, J=16.6, 7.1 Hz, 1H),
3.63-3.57 (m, 1H), 3.43 (dd, J=9.6, 5.6 Hz, 1H), 2.37 (s, 3H), 2.11
(td, J=12.2, 5.9 Hz, 1H), 1.74 (dq, J=13.8, 7.1 Hz, 1H); ESI MS
m/z=372.2 (M+1)
Example 317
(S)-1-(3-methyl-6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-
-2-yl)pyrrolidin-3-amine 317
[0487] Following the procedures as described in Examples 241, 243,
287, and starting with
3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)e-
thoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and (S)-tert-butyl
piperidin-3-ylcarbamate, 317 was obtained as an off-white solid (11
mg, 38%) over three steps. 1H NMR (400 MHz, DMSO) .delta. 9.27 (d,
J=2.1 Hz, 1H), 9.18 (s, 1H), 9.12 (s, 1H), 8.59 (dd, J=4.7, 1.3 Hz,
1H), 8.41 (d, J=8.0 Hz, 1H), 7.53 (dd, J=7.9, 4.7 Hz, 1H),
7.49-7.43 (m, 2H), 3.89-3.81 (m, 2H), 3.81-3.73 (m, 1H), 3.63-3.55
(m, 1H), 3.45-3.41 (m, 1H), 2.37 (s, 3H), 2.10 (td, J=12.3, 5.9 Hz,
1H), 1.74 (dq, J=14.0, 7.1 Hz, 1H); ESI MS m/z=372.2 (M+1)
Example 318
(S)-1-(3-bromo-6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin--
2-yl)pyrrolidin-3-ol 318
[0488] Following the procedures as described in Example 241 and
starting with
3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsi-
lyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and
(S)-pyrrolidin-3-ol, 318 was obtained as an off-white solid (1.8
mg, 3.0%) over two steps. 1H NMR (400 MHz, DMSO) .delta. 9.29-9.18
(m, 2H), 9.00 (s, 1H), 8.60 (d, J=4.6 Hz, 1H), 8.40 (d, J=8.0 Hz,
1H), 7.93 (d, J=8.0 Hz, 1H), 7.54 (dd, J=8.0, 4.7 Hz, 1H), 7.46 (d,
J=8.0 Hz, 1H), 5.75 (s, 1H), 5.01 (d, J=3.5 Hz, 1H), 4.45 (s, 1H),
4.11-4.00 (m, 2H), 3.90-3.81 (m, 1H), 3.63 (d, J=10.7 Hz, 1H), 2.06
(dd, J=8.4, 4.2 Hz, 1H), 1.95 (s, 1H); ESI MS m/z=437.1 (M+1)
Example 327
(S)-1-(3-ethyl-6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin--
2-yl)piperidin-3-amine 327
##STR00520##
[0490] (S)-tert-butyl
1-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3-
,4-c]pyridin-3-yl)-3-vinylpyridin-2-yl)piperidin-3-ylcarbamate
(59.18 mg, 0.09426 mmol) and palladium hydroxide on carbon 20%
(0.2:0.8, Palladium hydroxide:carbon black, 6.619 mg) in Ethanol
(30 mL) in a round bottom flask was vacuumed and connected to a
Hydrogen balloon. The mixture was stirred at room temperature over
the weekend. The reaction mixture was filtered through Celite. The
filtrate was concentrated to afford (S)-tert-butyl
1-(3-ethyl-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-py-
razolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-3-ylcarbamate,
which was dissolved in Trifluoroacetic Acid (3 mL) and Methylene
chloride (3 mL), and treated with Trifluoromethanesulfonic acid
(83.4 uL, 0.943 mmol) and Triethylsilane (150.6 uL, 0.943 mmol).
The resulting mixture was stirred at room temperature overnight.
The mixture was then concentrated, and the residue was purified by
reverse phase HPLC to afford 327 as an off-white solid (5.8 mg,
15%) over two steps. 1H NMR (400 MHz, DMSO) .delta. 9.31 (s, 1H),
9.20 (s, 1H), 9.13 (s, 1H), 8.59 (d, J=4.5 Hz, 1H), 8.46 (d, J=8.0
Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.53 (dd,
J=8.0, 4.8 Hz, 1H), 3.60 (d, J=11.4 Hz, 2H), 2.86 (dt, J=20.8, 9.5
Hz, 2H), 2.70 (dd, J=18.0, 10.0 Hz, 2H), 1.95 (d, J=12.5 Hz, 1H),
1.84 (d, J=13.1 Hz, 1H), 1.80-1.69 (m, 1H), 1.26 (t, J=7.5 Hz, 3H);
ESI MS m/z=400.2 (M+1)
Example 328
(S)-1-(3-isopropyl-6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyri-
din-2-yl)piperidin-3-amine 328
[0491] (S)-tert-butyl
1-(3-(prop-1-en-2-yl)-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)me-
thyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-3-ylcarbamate
(60.50 mg, 0.09426 mmol) and palladium hydroxide on carbon 20%
(0.2:0.8, Palladium hydroxide:carbon black, 6.619 mg) in Ethanol
(30 mL) in a round bottom flask was vacuumed and connected to a
Hydrogen balloon. The mixture was stirred at room temperature over
the weekend. The reaction mixture was filtered through Celite. The
filtrate was concentrated to afford (S)-tert-butyl
1-(3-isopropyl-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1-
H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-3-ylcarbamate,
which was dissolved in Trifluoroacetic Acid (3 mL) and Methylene
chloride (3 mL), and treated with Trifluoromethanesulfonic acid
(83.4 uL, 0.943 mmol) and Triethylsilane (150.6 uL, 0.943). The
resulting mixture was stirred at room temperature overnight. The
mixture was then concentrated, and the residue was purified by
reverse phase HPLC to afford 328 as an off-white solid (8.2 mg,
21%) over two steps. 1H NMR (400 MHz, DMSO) .delta. 9.31 (d, J=2.1
Hz, 1H), 9.22 (s, 1H), 9.06 (s, 1H), 8.61 (dd, J=4.7, 1.3 Hz, 1H),
8.45 (d, J=8.0 Hz, 1H), 8.32 (s, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.82
(d, J=7.9 Hz, 1H), 7.54 (dd, J=8.0, 4.8 Hz, 1H), 2.90 (d, J=9.1 Hz,
2H), 2.00 (d, J=12.6 Hz, 1H), 1.90 (d, J=13.4 Hz, 1H), 1.76 (dd,
J=24.1, 11.0 Hz, 1H), 1.46-1.34 (m, 1H), 1.25 (t, J=6.9 Hz, 6H);
ESI MS m/z=414.2 (M+1)
Example 901
Pim Kinase Binding Activity
[0492] PIM-1, PIM-2, and PIM-3 enzymes were generated as fusion
proteins expressed in bacteria and purified by IMAC column
chromatography (Sun, X., Chiu, J. F., and He, Q. Y. (2005) Expert
Rev. Proteomics, 2:649-657). A fluorescent-labeled Pim-specific
peptide substrate, was custom synthesized by American Peptide
Company (Sunnyvale, Calif.). Reaction Buffer contained 10 mM HEPES,
pH 7.2, 10 mM MgCl.sub.2, 0.01% Tween 20, 2 mM DTT. Termination
Buffer contained 190 mM HEPES, pH 7.2, 0.015% Brij-35, 0.2% Coating
Reagent 3 (Caliper Life Sciences, Hopkinton, Mass.), 20 mM EDTA.
Separation Buffer contained 100 mM HEPES, pH 7.2, 0.015% Brij-35,
0.1% Coating Reagent 3, 1:200 Coating Reagent 8 (Caliper Life
Sciences, Hopkinton, Mass.), 10 mM EDTA and 5% DMSO.
[0493] PIM reactions were carried out in a final volume of 10 .mu.L
per well in a 384-well plate. A standard enzymatic reaction,
initiated by the addition of 5 .mu.L 2.times.ATP and test compound
to 5 .mu.L of 2.times. enzyme and FAM-peptide, contained 20 pM
PIM-1, 50 pM PIM-2, or 55 pM PIM-3, 1 .mu.M FAM-peptide, and 10
.mu.M ATP, in Reaction Buffer. After 90 minutes of incubation at
room temperature, the phosphorylation reaction was stopped by the
addition of 10 .mu.L Termination Buffer. The product and substrate
in each independent reaction were separated on a 12-sipper
microfluidic chip (Caliper Life Sciences, Hopkinton, Mass.) run on
a Caliper LC3000.RTM. (Caliper Life Sciences, Hopkinton, Mass.).
The separation of product and substrate was optimized by choosing
voltages and pressure using Caliper's Optimizer software
(Hopkinton, Mass.). The separation conditions used a downstream
voltage of -500V, an upstream voltage of -2150V, and a screening
pressure of -1.2 psi. The product and substrate fluorophore were
excited at 488 nm and detected at 530 nm. Substrate conversion was
calculated from the electropherogram using HTS Well Analyzer
software (Caliper Life Sciences, Hopkinton, Mass.). Ki values for
the test compound were calculated.
Example 902
In Vitro Cell Proliferation Potency Assays
[0494] BaF3 parental line was obtained from the DSMZ repository.
BaF3 lines transfected with PIM-1 or PIM-2 were generated. Mouse
IL-3 was purchased from R&D Systems. G418 was purchased from
Clontech. Media for BaF3 parental line contained RPMI, 10% FBS, 2
mM L-Glutamine, 2 ng/mL mIL-3. Media for BaF3 PIM1 & 2 lines
contained RPMI, 10% FBS, 2 mM L-Glutamine, 250 .mu.g/mL. Media for
MM1.S (multiple myeloma cells) line contained RPMI, 10% FBS, 2 mM
L-Glutamine.
[0495] BaF3, a murine interleukin-3 dependent pro-B cell line,
parental cells, BaF3 PIM1 cells, BaF3 PIM-2 cells, and MM1.S
(multiple myeloma) cells were seeded at 2 k/well, 5 k/well, 5
k/well, and 10 k/well respectively, in a 384-well plate, at 45
.mu.L/well. Test compound was added at 5 .mu.L/well. BaF3 cells
(parental and transfected) were incubated overnight, while MM1.S
cells were incubated for 72 hours at 37.degree. C., 5% CO.sub.2.
Cell Titer Glo Reagent (Promega) was added at 50 .mu.L/well, the
plates were incubated for 30 minutes, and their luminescence read
on an HT Analyst. IC.sub.50/EC.sub.50 values for the test compound
were calculated.
[0496] Representative compounds of the present invention were
tested as described above and found to exhibit a
Ki/IC.sub.50/EC.sub.50 in the in vitro cell proliferation potency
assays, as shown below.
TABLE-US-00003 Prolif. BaF3 IL3 Prolif. BaF3 PIM-1 Prolif. MM1S ATP
No. (IC50) .mu.M (IC50) .mu.M (EC50) .mu.M 116 13.7 21.3 117 12.9
18.8 129 5.6 5.2 144 3.3 0.13 2.2 147 3.9 0.368 0.0604 149 1.5
0.261 0.166 152 2.7 0.0471 0.631 153 2.5 0.028 0.436 161 1.4 0.731
0.281 173 5.7 0.251 0.376 190 1.8 0.159 0.0672 241 1.3 0.584 0.0573
248 1.6 0.336 0.201 249 2.5 0.518 0.191 270 13.1 0.478 0.707 307
1.4 0.0671 0.141 316 1.0 0.0628 0.114 349 3.4 0.681 0.393 350 3.6
0.188 0.287 356 5.4 0.0766 0.638 357 4.9 0.709 0.244 376 4.1 0.0309
0.356 377 5.3 0.0637 0.23 381 2.2 0.129 0.228 382 17 0.274 3.2 383
1.3 0.11 0.17 390 5.7 0.0585 0.13 505 2.3 0.0402 0.0979
[0497] Although the foregoing invention has been described in some
detail by way of illustration and example for purposes of clarity
of understanding, the descriptions and examples should not be
construed as limiting the scope of the invention. The disclosures
of all patent and scientific literature cited herein are expressly
incorporated in their entirety by reference.
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